Condensed heterocyclic compounds and pharmaceutical use thereof

ABSTRACT

The invention relates to compounds of the formula  (* CHEMICAL STRUCTURE *) I wherein R1 is hydrogen. acyl, lower-alkyl or -CHO, -CH2OR10, -COR7 or OR13; R2, R3 and R4 are, independently, hydrogen, lower-alkyl, lower-alkoxy or halogen; R5 and R5 are, independently, hydrogen or lower-alkyl; R7 is hydroxy, lower-alkoxy or NR8R9; R8 and R9 are, independently, hydrogen or lower-alkyl; X and Y are, independently, &gt;CR14R15, -O-, -S-, &gt;SO, &gt;SO2 or &gt;NR18; R10 and R18 are, independently, hydrogen, lower-alkyl or acyl; M is -C(R11)=C(R12)-, -CONH- or -NH-CO-; R11, R12, R14 and R15 are, independently, hydrogen or lower-alkyl, R13 is hydrogen, lower-alkoxycarbonyl or lower- alkyl, which can be substituted by amino, mono-alkylamino, di-alkylamino, morpholino, thiomorpholino or piperazino; and n is 1, 2, 3 or 4; with the proviso that at least one of X and Y comprises a hetero atom and that n is 1, 3 or 4 when X contains a hetero atom, Y is &gt;C(CH3)2 and R1 is lower-alkyl or -CH2OR10 or -COR7, or a salt of a compound of formula I, when R1 is carboxy. The compounds of formula I are useful in the treatment and prophylaxis of neoplasms, dermatoses and ageing of the skin.

This is a division of application Ser. No. 07/696,812 filed May 28,1991, now U.S. Pat. No. 5,164,387, which was a division of applicationSer. No. 07/377,510 filed Jul. 10, 1989, now U.S. Pat. No. 5,037,825.

BRIEF SUMMARY OF THE INVENTION

The invention relates to condensed heterocyclic compounds of the formula##STR2## wherein R¹ is hydrogen, acyl, lower-alkyl or a group --CHO,--CH₂ OR¹⁰, --COR⁷ or OR¹³ ; R², R³ and R⁴ are, independently, hydrogen,lower-alkyl, lower-alkoxy or halogen; R⁵ and R⁶ are, independently,hydrogen or lower-alkyl; R⁷ is hydroxy, lower-alkoxy or NR⁸ R⁹ ; R⁸ andR⁹ are, independently, hydrogen or lower-alkyl; X and Y are,independently. >CR¹⁴ R¹⁵, --O--, --S--, >SO, >SO₂ or >NR¹⁸ ; R¹⁰ and R¹⁸are, independently, hydrogen, lower-alkyl or acyl; M is--C(R¹¹)═C(R¹²)--, --CONH-- or --NH--CO--; R¹¹, R¹², R¹⁴ and R¹⁵ are,independently, hydrogen or lower-alkyl, R¹³ is hydrogen,lower-alkoxycarbonyl or lower-alkyl, which can be substituted by amino,mono-alkylamino, di-alkylamino, morpholino, thiomorpholino orpiperazino; and n is 1, 2, 3 or 4; with the proviso that at least one ofX and Y comprises a hetero atom and that n is 1, 3 or 4 when X containsa hetero atom, Y is >C(CH₃)₂ and R¹ is lower-alkyl or --CH₂ OR¹⁰ or--COR⁷, and salts of the compounds of formula I, when R¹ is a carboxygroup.

In another aspect, the invention relates to a process for thepreparation of the compounds of formula I, pharmaceutical preparationsbased on the compounds of formula I, the compounds of formula I in thetreatment and prophylaxis of neoplasms, dermatoses and aging of the skinas well as the use of the compounds of formula I in the preparation ofpharmaceutical preparations for the treatment and prophylaxis of suchdisorders.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to condensed heterocyclic compounds of the formula##STR3## wherein R¹ is hydrogen, acyl, lower-alkyl or a group --CHO,--CH₂ OR¹⁰, --COR⁷ or OR¹³ ; R², R³ and R⁴ are, independently, hydrogen,lower-alkyl, lower-alkoxy or halogen; R⁵ and R⁶ are, independently,hydrogen or lower-alkyl; R⁷ is hydroxy, lower-alkoxy or NR⁸ R⁹ ; R⁸ andR⁹ are, independently, hydrogen or lower-alkyl; X and Y are,independently, >CR¹⁴ R¹⁵, --O--, --S--, >SO, >SO₂ or >NR¹⁸ ; R¹⁰ and R¹⁸are, independently, hydrogen, lower-alkyl or acyl; M is--C(R¹¹)═C(R¹²)--, --CONH-- or --NH--CO--; R¹¹, R¹², R¹⁴ and R¹⁵ are,independently, hydrogen or lower-alkyl, R¹³ is hydrogen,lower-alkoxycarbonyl or lower-alkyl, which can be substituted by amino,mono-alkylamino, di-alkylamino, morpholino, thiomorpholino orpiperazino; and n is 1, 2, 3 or 4; with the proviso that at least one ofX and Y comprises a hetero atom and that n is 1, 3 or 4 when X containsa hetero atom, Y is >C(CH₃)₂ and R¹ is lower-alkyl or --CH₂ OR¹⁰ or--COR⁷, and salts of the compounds of formula I, when R¹ is a carboxygroup.

Furthermore, the invention relates to a process for the preparation ofthe compounds of formula I, pharmaceutical preparations based on thecompounds of formula I, the compounds of formula I in the treatment andprophylaxis of neoplasms, dermatoses and aging of the skin as well asthe use of the compounds of formula I in the preparation ofpharmaceutical preparations for the treatment and prophylaxis of suchdisorders.

The term "lower" denotes groups with 1-6 C atoms. The terms "alkyl", and"alkoxyl" groups denote straight-chain or branched hydrocarbons, such asmethyl, ethyl, propyl, isopropyl, butyl, sec.-butyl or tert.-butyl andmethoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy andtert.-butoxy, respectively. Examples of acyl groups are alkanoyl groups,preferably lower-alkanoyl groups such as acetyl, propionyl, butyryl,pivaloyl and caproyl; or aroyl groups such as benzoyl, p-nitrobenzoyland toluoyl; or aralkanoyl groups, for example, phenylalkanoyl, such asphenylacetyl.

A preferred group of compounds of formula I comprises those in which Yis --O--, --S--, >SO, >SO₂ or >NR¹⁸. Furthermore, compounds of formula Iin which X and Y are --O--, --S--, >SO, >SO₂ or >NR¹⁸, especially thosein which X and Y are --S--, are preferred. Preferably, n is 2 or 3,especially 3. M preferably is --C(R¹¹)═C(R¹²), especially --C(CH₃)═CH--;and --CONH--.

The compounds of formula I can be prepared in accordance with theinvention by

a) reacting a compound of the formula ##STR4## with a compound of theformula ##STR5## wherein either A is the residue --CH(R¹¹)P⁺ (Q)₃ Z⁻ or--CH(R¹¹)--P(O)(OAlk)₂ and B is R¹² --CO--; or A is R¹¹ --CO-- and B isthe residue --CH(R¹²)P⁺ (Q)₃ Z⁻ or --CH(R¹² )--P--(O)(OAlk)₂ ; Q isaryl; Z⁻ is an anion of an organic or inorganic acid; Alk is loweralkyl; and R¹⁶ is R¹ with the exception of the formyl, carboxyl, hydroxyand hydroxymethyl group; or

b) reacting a compound of the formula ##STR6## with a compound of theformula ##STR7## wherein either D is a carboxyl group or a reactivederivative thereof and E is an amino group or D is an amino group and Eis a carboxyl group or a reactive derivative thereof and R¹⁹ is aresidue R¹ with the exception of the carboxyl, hydroxymethyl and hydroxygroup;

c) reacting a compound of the formula ##STR8## with a compound of theformula ##STR9## wherein either F is --CH(R¹¹)MgHal and G is R¹²--C(O)--; or F is R¹² --C(O)-- and G is --CHC(R¹²)MgHal; Hal is halogenand R¹⁷ is hydrogen, lower-alkyl or --OR¹³ ; and whereby the remainingsymbols are as described earlier in formulas II-VII; and dehydrating thereaction product;

whereupon, if desired, in the resulting reaction product of formula I,the residue R¹ is functionally modified and/or the sulfur atom is acompound I wherein X and/or Y is --S-- is oxidized to a sulfoxyl orsulfonyl group.

The reaction of the compounds II and III, in accordance with processvariant a), can be carried out according to the known Wittig or Hornerreaction.

In the case of the Wittig reaction, that is, using a compound of formulaII wherein A=--CH(R¹¹)P⁺ (Q)₃ Z⁻ or of formula III wherein B=--CH(R¹²)P⁺(Q)₃ Z⁻, the components are reacted with one another in the presence ofan acid-binding agent, for example, in the presence of a strong basesuch as for example, butyllithium, sodium hydride or the sodium salt ofdimethyl sulfoxide, or potassium tertbutylate, but especially in thepresence of an ethylene oxide which is optionally substituted bylower-alkyl such as 1,2-butylene is oxide, optionally in a solvent, forexample, in an ether such as diethyl ether or tetrahydrofuran or in anaromatic hydrocarbon such as benzene, at a temperature in the range ofbetween room temperature and the boiling point of the reaction mixture.

Of the inorganic acid anions Z⁻, the chloride or bromide ion or thehydrosulfate ion is preferred and of the organic acid anions thetosyloxy ion is preferred. The aryl residue Q is preferably phenyl.

In the case of the Horner reaction, that is, using a compound of formulaII wherein A=--CH(R¹¹)P(O)(OAlk)₂ or of formula III whereinB=--CH(R¹²)P(O)(OAlk)₂, the components are condensed with the aid of abase and preferably in the presence of an inert organic solvent, forexample, with the aid of sodium hydride in benzene, toluene,dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, oralso with the aid of a sodium alcoholate in an alkanol, for example,sodium methylate in methanol, at a temperature range of between 0° andthe boiling point of the reaction mixture. The alkoxy residues in A andB are preferably lower alkoxy residues of 1-6 carbon atoms such asmethoxy or ethoxy.

Compounds of formula I wherein M is --C(R¹¹)═C(R¹²)-- are obtained inaccordance with process variant a).

The reaction of a compound IV with a compound V in accordance withprocess variant b), can be carried out according to known methods forthe acylation of amines. Preferably, a compound of formula IV wherein Dis a carboxylic acid halide group, for example, the group --COCl, isreacted with a compound of formula V wherein E is --NH₂ to give acompound of formula I wherein M is --CONH-- or an amine of formula IV isreacted with a carboxylic acid halide of formula V to give a compound offormula I wherein M is --NH--CO--. The acylations are convenientlycarried out in the presence of a base, for example, an organic base suchas pyridine.

The reaction of the compounds of formulas VI and VII in accordance withprocess variant c), can be carried out in a known manner under theconditions of a Grignard reaction, for example, in an ether such asdiethyl ether or tetrahydrofuran at room temperature and subsequentwater-cleavage with an acidic agent, for example, with an organic acidsuch as p-toluenesulfonic acid. According to this process variant, thereare obtained compounds of formula I wherein M is --C(R¹¹)═C(R¹²)-- andR¹ is R¹⁷ as described above.

As functional modifications of a substituent R¹ in a resulting compoundof formula I, there come into consideration, for example, thesaponification of a carboxylic acid ester or its reduction to thehydroxymethyl group. The hydroxymethyl group can also be oxidized to theformyl group or can be esterified or etherified. Furthermore, a carboxylgroup can be converted into a salt, an ester, an amide or thehydroxymethyl group.

All of these modifications can be carried out according to knownmethods.

A carboxylic acid ester of formula I can be amidated directly, asdescribed hereinafter, or can be hydrolyzed in a known manner, forexample, by treatment with alkalis, especially by treatment withaqueous-alcoholic sodium hydroxide solution or potassium hydroxidesolution at a temperature in the range of between room temperature andthe boiling point of the reaction mixture, to the carboxylic acid whichcan be amidated via an acid halide.

A carboxylic acid of formula I can be converted in a known manner, forexample, by treatment with thionyl chloride or phosphorus trichloride intoluene or oxalyl chloride in dimeihylformamide/benzene, into the acidchloride which can be converted by reaction with alcohols into esters orwith amines into the corresponding amide.

A carboxylic acid ester of formula I can be converted, for example, bytreatment with lithium amide directly into the corresponding amide. Thelithium amide is advantageously reacted with the respective ester atroom temperature.

A carboxylic acid or a carboxylic acid ester of formula I can be reducedin a known manner to the corresponding alcohol of formula I. Thereduction is advantageously carried out with the aid of a metal hydrideor alkyl metal hydride in an inert solvent. Mixed metal hydrides such aslithium aluminum hydride or bis-[methoxy-ethoxy]-sodium aluminumdihydride have been found to be particularly suitable hydrides. Assolvents there can be used, inter alia, ethers, tetrahydrofuran ordioxane when lithium aluminum hydride is used; and ethers, hexane,benzene or toluene when diisobutylaluminum hydride orbis-[methoxy-ethoxy]-sodium aluminum dihydride is used.

An alcohol of formula I can be etherified, for example, in the presenceof a base, preferably in the presence of sodium hydride, in an organicsolvent such as dioxan, tetrahydrofuran, 1,2-dimethoxyethane,dimethylformamide, at a temperature in the range of between 0° and roomtemperature with an alkyl halide, for example, with methyl iodide.

An alcohol of formula I can also be esterified by treatment with analkanoyl halide or anhydride, conveniently in the presence of a base,for example, in the presence of pyridine or triethylamine, at atemperature in the range of between room temperature and the boilingpoint of the reaction mixture.

The carboxylic acids of formula I form salts with bases, especially withthe alkali metal hydroxides, preferably with sodium hydroxide orpotassium hydroxide.

A compound of formula I wherein X and/or Y is --S-- can be oxidizedusing known methods to give a compound of formula I wherein X and/or Yis ═SO or ═SO₂. The oxidation to-the sulfoxide group can be carried outwith oxidizing agents such as periodates, for example, NaIO₄ or withorganic peroxides such as m-chloroperbenzoic acid. The oxidation withorganic peracids is carried out using about one equivalent of peracid inorder to obtain a sulfoxide compound (X/Y=SO), whereas the use of twoequivalents of peracid leads to sulfones (X/Y=SO₂).

The compounds of formula I wherein M contains a C--C double bond can bepresent in the trans or cis form. When prepared, they occurpredominantly in the trans form. Where desired, cis components which maybe obtained can be separated or isomerized in a known manner.

The compounds of formulas II-V, which are used as starting materials forthe preparation of the compounds of formula I, insofar as they are notknower or are not described hereinafter, can be prepared in analogy toknown methods or to the methods described hereinafter.

The compounds of formula I and their physiologically compatible saltsare pharmacodynamically valuable compounds. They can be used for thetopical and systemic therapy of benign and malignant neoplasms, ofpremalignant lesions as well as, further, for the systemic and topicalprophylaxis of the said conditions.

Furthermore, they are suitable for the topical and systemic therapy ofacne, psoriasis and other dermatoses which are accompanied by anintensified or pathologically altered cornification, as well as ofinflammatory and allergic dermatological conditions and of light-damaged(aged) skin. Further, they can also be used for the control of mucousmembrane disorders with inflammatory or degenerative or metaplasticchanges. In the papilloma test, (Europ. J. Cancer Vol. 10, pp. 731-737,1974) ethyl p-[2--(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-yl)propenyl]benzoate (Example 1) andp-[2-(1,2,3,4-tetrahydro-1,1,4-trimethyl-7-quinolinyl)propenyl]benzoicacid (Example 5) in a dosage of 6 mg/kg/week showed a papillomaregression of 66 and 42%, respectively;p[2-(3,4-dihydro-4,4-dimethyl-2H-1-thiobenzopyran-7-yl) propenyl]benzoicacid (Example 3) in a dosage of 3 mg/kg/week showed a papillomaregression of 61% and ethylp[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]benzoatein a dosage of 50 mg/kg/week showed a papilloma regression of 50%.

The compounds of formula I can also be used for the treatment ofinflammatory, allergic, rheumatic and immunological disorders in a widevariety-of organs. Examples of such disorders are: primary-chronicpolyarthritis, spondylarthritis ancylopoetica, osteoarthritides,arthritides and arthroses; eczemas, a topical dermatitis, allergicrhinitis, bronchial asthma; autoimmune disorders, for example, Lupuserythematosus and Reiter's syndrome.

The compounds of formula I and their aforementioned salts canaccordingly be used as medicaments, for example, in the form ofpharmaceutical preparations.

The compositions can be administered enterally, parenterally ortopically. For enteral administration suitable for example, compositionsin the form of tablets, capsules, dragees, syrups, suspensions,solutions and suppositories. Preparations in the form of infusions orinjections are suitable for parenteral administration.

The dosages at which in the preparations are administered can varyaccording to the mode of administration and route of administration aswell as according to the requirements of the host requiring suchtreatment.

In the case of oral administration of the compounds in accordance withthe invention, dosages of about 0.1-100 mg/kg per day, preferably 0.5-50mg/kg, come into consideration for adults.

The preparations can be administered in one or several doses. Capsulescontaining about 5-500 mg of active ingredient are a preferredadministration form.

The preparations can contain inert or pharmacodynamically activeadditives. Tablets or granulates, for example, can contain a series ofbinding agents, filler materials, carrier substances or diluents. Liquidpreparations can be present, for example, in the form of sterilesolution which is miscible with water. Capsules can contain a fillermaterial or thickening agent in addition to the active ingredient.Furthermore, flavor-improving additives as well as the substancesusually used as preserving, stabilizing, moisture-retaining andemulsifying agents, salts for varying the osmotic pressure, buffers andother additives,can also be present.

The previously mentioned carrier substances and diluents can be organicor inorganic substances, for example, of water, gelatin, lactose,starch, magnesium stearate, talc, gum arabic, polyalkylene glycols andthe like. It is a prerequisite that all adjuvants used in thepreparation of the preparations are non-toxic.

For topical use, the active ingredients are conveniently used in theform of salves, tinctures, creams, solutions, lotions, sprays,suspensions and the like. Salves and creams as well as solutions arepreferred, These preparations intended for topical use can be preparedby mixing the aforementioned compounds and salts as active ingredientswith non-toxic, inert, solid or liquid carriers which are usual in suchpreparations and which are suitable for topical treatment.

For topical use, conveniently suitable preparations comprise about0.1-5%, preferably 0.3-2%, solutions as well as about 0.1-5%, preferablyabout 0.3-2%, salves or creams.

If desired, an antioxidant, for example, tocopherol,N-methyl-γ-tocopheramine as well as t-butyl-hydroxyanisole ort-butyl-hydroxytoluene, can be admixed with the preparations.

EXAMPLE 1

0.5 g of a 50% suspension of sodium hydride in mineral oil weresuspended in 15 ml of dimethyl sulfoxide and treated under argon with asolution of 3.2 g of diethyl (4-carbethoxybenzyl)phosphonate in 10 ml ofdimethyl sulfoxide. The mixture was subsequently heated to 40° C. for 20minutes, cooled to room temperature, a solution of 0.87 g of3,4-dihydro-4,4-dimethyl-7-acetyl-2H-1-benzopyran in 5 ml of dimethylsulfoxide was added dropwise thereto and the mixture was heated to 40°C. for 1 hour. The reaction mixture obtained was poured on to ice/water,acidified with 1N hydrochloric acid and extracted repeatedly with ether.The organic phase was washed with water, dried and evaporated. There wasobtained a yellowish oil which, after filtration over a short column(silica gel, eluting agent hexane/ethyl acetate=9:1), crystallized fromhexane and yielded 0.9 g of ethylp-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-yl)propenyl]benzoate,m.p. 48°-50° C.

The 3,4-dihydro-4,4-dimethyl-7-acetyl-2H-1-benzopyran used as thestarting material can be prepared as follows:

A mixture of 20 g of 3-bromophenol, 92 g of ethyl acrylate and 1.8 ml ofTriton B (35% in methanol) was boiled at reflux overnight. Afterdistilling off the excess acrylate at normal pressure, the residue wasdistilled in a high vacuum. There were obtained 16.7 g of ethyl3-(m-bromophenoxy)propionate as a colorless oil, boiling point 107°-110°C./67 Pa.

4.4 g of Magnesium shavings were covered with 40 ml of ether and treatedover a period of 30 minutes with a solution of 32 g of methyl iodide in70 ml of ether. After boiling under reflux for an additional 30 minutes,a solution of 16.7 g of ethyl 3-(m-bromophenoxy)propionate in 70 ml ofbenzene was added dropwise thereto while cooling. The reaction mixturewas heated to reflux for 1.5 hours and subsequently treated with 210 mlof saturated ammonium chloride solution while cooling with ice. Afterrepeated extraction of the reaction mixture with ether, washing of theorganic with water, drying and evaporation there was obtained an oilwhich was purified further by filtration over a short column (SiO₂,eluting agent hexane/ethyl acetate=9:1). There were obtained 14 g of4-(m-bromo- phenoxy)-2-methyl-2-butanol as a colorless oil, boilingpoint 106° C./40 Pa.

9.8 g of Aluminum chloride were dissolved in 100 ml of nitromethane andtreated in the course of 40 minutes at room temperature with a solutionof 14 g of 4-(m-bromophenoxy)-2-methyl-2-butanol in 100 ml ofnitromethane. The mixture was stirred at room temperature for anadditional 1.5 hours, cooled to 0° C. and 200 ml of 2N hydrochloric acidand 300 ml of water were added dropwise thereto in succession.

After extraction of the reaction mixture with ether, drying andevaporation of the organic phase, the thus-obtained red-brown oil wasfirst filtered over a column (SiO₂, eluting agent hexane/ethylacetate=9:1) and subsequently distilled in a high vacuum. There wereobtained 8 g of 7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzopyran as acolorless oil, boiling point 82°-86° C./0.5 mm. This substance stillcontained some 5-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzopyran and wasused in this form in the next step.

1 g of Magnesium shavings was covered with 10 ml of absolutetetrahydrofuran and treated dropwise at 50°-60° C. using an ultrasonicsbath with a solution of 10 g of7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzopyran in 50 ml oftetrahydrofuran. Thereafter, the mixture was heated to 70° C. for anadditional 2 hours, cooled to 0° C. and a solution of 9.5 g ofacetaldehyde in 30 ml of tetrahydrofuran was added dropwise thereto. Themixture was stirred at room temperature for an additional hour, pouredon to ice/saturated ammonium chloride solution, extracted with ether,washed with water, dried and evaporated. After chromatography (silicagel, eluting agent hexane/ethyl acetate 4:1) there were obtained 6.9 gof 3,4-dihydro-α,4,4-trimethyl-7-(2H-1-benzopyran)methanol as a viscousoil.

5.9 g of 3,4-dihydro-α,4,4-trimethyl-7-(2H-1-benzopyran)-methanol weredissolved in 200 ml of methylene chloride and treated with 25 g ofmanganese dioxide. After stirring at room temperature for 3 hours, thereaction mixture was filtered and the filtrate was evaporated. Therewere obtained 5.8 g of 3,4-dihydro-4,4-dimethyl-7-acetyl-2H-1-benzopyranas a colorless oil.

EXAMPLE 2

0.5 g of the ethyl ester from Example 1 was dissolved in 20 ml ofethanol and treated with a solution of 0.8 g of potassium hydroxide in 5ml of water. After stirring at 50° C. for 2 hours, the mixture waspoured on to ice/water, acidified with 2N hydrochloric acid andextracted repeatedly with ethyl acetate. After washing the organic phasewith water, drying over sodium sulfate, evaporation and crystallizationfrom ethyl acetate, there were obtained 350 mg ofp-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-yl)propenyl]benzoicacid, m.p. 242°-244° C.

EXAMPLE 3

18.9 g of[1(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)ethyl]]triphenylphosphoniumbromide were suspended in 200 ml of 1,2-butylene oxide and heated atreflux for 16 hours with 5.7 g of ethyl 4-formyl-benzoate. Aftercooling, the clear reaction mixture was poured into a mixture ofmethanol and water (6:4), extracted three times with hexane, washed withmethanol/water (6:4) and water, dried and evaporated. The yellow oilobtained was filtered over silica gel (eluting agent hexane/ethylacetate 19:1) and crystallized from hexane/ethyl acetate. There wereobtained 5.9 g of ethylp-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)propenyl]benzoatein the form of colorless crystals, m.p. 64°-65° C.

1 g of the thus-obtained ester was dissolved in 20 ml of ethanol andtreated with a solution of 1.6 g of potassium hydroxide in 10 ml ofwater. After heating to 50° C. for 2 hours, the mixture was poured on toice, acidified with 2N hydrochloric acid and extracted repeatedly withethyl acetate. The crystalline residue obtained after evaporation wasrecrystallized from acetic acid. There was obtained 0.6 g ofp-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)propenyl]benzoicacid, m.p. 255°-257° C.

The phosphonium salt used as the starting material can be prepared asfollows:

36 g of 3-bromothiophenol were dissolved in 400 ml of dimethylformamide.After the addition of 27 g of finely powdered potassium carbonate and 29g of 3,3-dimethylallyl bromide, the mixture was stirred at roomtemperature for 1 hour, diluted with 500 ml of water, acidified with 3Nhydrochloric acid while cooling and extracted with ether. Theyellow-brown oil obtained after evaporation was distilled in a highvacuum. There were obtained 48 g of m-bromophenyl 3-methyl-2-butenylsulfide as a colorless liquid, boiling point 85° C./13.3 Pa.

46.5 g of this sulfide were dissolved in 800 ml of toluene and, afterthe addition of 45 g of p-toluenesulfonic acid monohydrate, boiled for10 hours on a water separator. The cooled reaction mixture was dilutedwith water, neutralized by the addition of aqueous sodium bicarbonatesolution and extracted with ethyl acetate. The yellow-brown oil obtainedafter evaporation of the solvent was distilled in a high vacuum. Therewere obtained 39 g of7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran as a slightlyyellowish oil, boiling point 90°-93° C./13.3 Pa. The compound containedabout 15% of 5-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran andwas used in this form in the next step.

1.85 g of Magnesium shavings were covered with 20 ml of absolutetetrahydrofuran. While heating to reflux, there was added dropwisethereto a solution of 10.8 g of the mixture obtained in the previousstep in 80 ml of tetrahydrofuran and the mixture was boiled untilpractically all of the magnesium had dissolved. After cooling to 0° C.,a solution of 8.5 g of acetaldehyde in 50 ml of tetrahydrofuran wasadded dropwise thereto and the mixture was stirred at room temperaturefor an additional 30 minutes. The reaction mixture was poured intoice-cold ammonium chloride solution, extracted with ethyl acetate,washed with water and evaporated. After filtration over silica gel(eluting agent hexane/ethyl acetate=19:1), there were obtained 13.5 g of3,4-dihydro-α,4,4-trimethyl-7-(2H-1-benzothiopyran)methanol as aslightly yellow, viscous oil.

This oil was dissolved in 250 ml of acetonitrile and treated with 23 gof triphenylpnosphine hydrobromide. After heating to 60° C. for 20hours, the reaction mixture was evaporated. The residue was taken upwith 500 ml of 80% aqueous ethanol and extracted three times withhexane. The ethanol solution was evaporated. The residue was dissolvedin methylene chloride, dried over sodium sulfate and evaporated. Therewas obtained a foamy residue which was converted by trituration withether into an amorphous, filterable substance, whereby 26 g of[1-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)-ethyl]triphenylphosphoniumbromide were obtained.

EXAMPLE 4

2.5 g of ethylp-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)propenyl]benzoatewere dissolved in 30 ml of chloroform and treated dropwise at 0° C. witha solution of 2.7 g of 90% m-chloroperbenzoic acid in 40 ml ofchloroform. Depending on the content of the peracid some morem-chloroperbenzoic acid must be added until the sulfoxide resulting asan intermediate has disappeared completely. The reaction mixture wasdiluted with chloroform, extracted twice with ice-cold dilute, aqueoussodium carbonate solution, washed twice with water, dried andevaporated. After chromatography of the crude product (silica gel,eluting agent hexane/ethyl acetate=4:1) and crystallization from ethylacetate/hexane, there were obtained 1.4 g of ethylp-[2-(3',4'-dihydro-4',4'-dimethyl-2'H-1-benzothiopyran-7'-yl)propenyl]benzoate1',1'-dioxide in the form of colorless crystals, m.p. 90°-91° C.

Hydrolysis of the thus-obtained ethyl ester with potassium hydroxide inaqueous-ethanolic solution in analogy to Example 3 gave, afterrecrystallization from tetrahydrofuran/ethyl acetate/hexane,p-[2-(3',4'-dihydro-4',4'-dimethyl-2'H-1-benzothiopyran-7'-yl)propenyl]benzoicacid 1',1'-dioxide in the form of colorless crystals, m.p. 163°-265° C.

EXAMPLE 5

2.9 g of a 50% suspension of sodium hydride in mineral oil weresuspended in 30 ml of dimethylformamide after two-fold washing withpentane and treated dropwise at room temperature with a solution of 17.3g of diethyl (4-carbethoxybenzyl)phosphonate in 50 ml ofdimethylformamide. After stirring at room temperature for 1 hour, asolution of 5 g of 1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinylmethyl ketone in 50 ml of dimethylformamide was added dropwise thereto.The reaction mixture was heated to 50° C. for 1 hour, poured on toice/water and extracted with ethyl acetate. The brownish oil obtainedafter drying and evaporation of the organic phase was chromatographed(silica gel, eluting agent hexane/ethyl acetate=9:1) and gave 4.2 g ofethylp-[2-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl)propenyl]benzoateas a slightly yellow, viscous oil.

3.2 g of this oil were dissolved in 30 ml of ethanol and treated with asolution of 5 g of potassium hydroxide in 20 ml of water. After heatingto 50° C. for 2 hours, the mixture was poured on to ice/water. Thesolution was adjusted to pH 5 by the addition of 1N hydrochloric acidand extracted with methylene chloride. The crude product obtained afterdrying and evaporation of the organic phase was recrystallized fromethyl acetate/hexane and gave 1.4 g ofp-[2-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl)propenyl]benzoicacid in the form of grey crystals, m.p. 194°-196° C.

The 1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl methyl ketone usedas the starting material can be prepared as follows:

55.4 g of 3-bromoaniline were dissolved in 300 ml of hexane and treatedwith 76 ml of triethylamine. A solution of 40 g of 3,3-dimethylacrylylchloride in 300 ml of hexane was added dropwise thereto while coolingwith ice. After boiling at reflux for 3 hours, the mixture was poured onto ice/water and extracted with ether. The organic phase was washed withwater, dried and evaporated. There was obtained a brown oil which wasdistilled in a high vacuum. The yield amounted to 51 g ofN-(3-bromophenyl)-3,3-dimethyl-acrylamide (yellow oil), boiling point146°-152° C./93 Pa.

28.7 g of powdered potassium hydroxide were suspended in 300 ml ofdimethyl sulfoxide and a solution of 32.6 g ofN-(3-bromophenyl)-3,3-dimethyl-acrylamide in 200 ml of dimethylsulfoxide(DMSO) was added dropwise thereto. The mixture was stirred at roomtemperature for 30 minutes and subsequently a solution of 27.5 g ofmethyl iodide in 150 ml of DMSO was added dropwise thereto. After 2.5hours the mixture was poured on to 1 l of ice/water and extracted withethyl acetate. The organic phase was washed repeatedly with water, driedand evaporated. The oily residue was distilled in a high vacuum. Therewere obtained 29.3 g ofN-methyl-N-(3-bromophenyl)-3,3-dimethyl-acrylamide as a slightly yellowoil, boiling point 112°-114° C./67 Pa.

29.3 g of this oil were dissolved in 1 l of high-boiling petroleumether. 30 g of Aluminum chloride were added thereto while stirring andthe mixture was subsequently boiled at reflux for 3 hours. After coolingto 0°-5° C., 700 ml of 2N hydrochloric acid were slowly added dropwisethereto. The mixture was diluted with water and extracted with ether.The yellow-brown oil obtained after drying and evaporation of thesolvent was a 1:1 mixture of 5-bromo- and7-bromo-3,4-dihydro-1,4,4-trimethyl-2(1H)quinolinone. By columnchromatography (silica gel, eluting agent hexane/ethyl acetate 9:1)there was first eluted the 7-bromo compound which crystallized fromhexane, yield 4.2 g, melting point 92°-94° C.

14.2 g of the 7-bromo compound were dissolved in 300 ml oftetrahydrofuran and treated dropwise at 0° C. with a solution of 5.7 mlof borane-dimethyl sulfide complex (about 10 molar in excess dimethylsulfide) in 250 ml of tetrahydrofuran. The reaction mixture wassubsequently heated to reflux for 2.5 hours under argon, cooled to 0° C.and treated dropwise in succession with 700 ml of methanol and 300 ml of6N hydrochloric acid. After 30 minutes, the mixture was evaporated in awater-jet vacuum. The liquid residue was treated with ice, made alkalineby the addition of ice-cold 3N sodium hydroxide solution and extractedwith ether. After drying and evaporation of the solvent, there wasobtained a yellowish oil which was distilled in a high vacuum andyielded 11.8 g of 7-bromo-1,2,3,4-tetrahydro-1,4,4-trimethylquinoline asa colorless oil, boiling point 124°-127° C./120 Pa. The compoundsolidified upon standing in a refrigerator.

2 g of Magnesium shavings were covered with 20 ml of tetrahydrofuran. Asolution of 20.8 g of7-bromo-1,2,3,4-tetrahydro-1,4,4-trimethylquinoline in 80 ml oftetrahydrofuran was added dropwise thereto at 55°-60° C. using anultrasonics bath. Thereafter, the mixture was boiled at reflux for anadditional 2 hours, cooled to 0° C. and a solution of 10 g ofacetaldehyde in 80 ml of tetrahydrofuran was added dropwise thereto.After stirring at room temperature for 1 hour, the mixture was poured onto ice/saturated ammonium chloride solution and extracted with ether.The oil obtained after drying and evaporation of the solvent wasfiltered over a silica gel column (eluting agent hexane/ethyl acetate9:1) and gave 14.5 g of1,2,3,4-tetrahydro-α,1,4,4-tetramethyl-7-quinolinemethanol as ayellowish oil.

5.5 g of oxalyl chloride were dissolved in 50 ml of methylene chloride.At -60° C. there was added dropwise thereto a mixture of 6 ml ofdimethyl sulfoxide and 35 ml of methylene chloride and, after 5 minutes,a solution of 8.5 g of the oil obtained in the previous step in 85 ml ofmethylene chloride. The mixture was stirred for an additional 15 minutesat -60° C. and there were then added dropwise thereto at thistemperature 28 ml of trimethylamine. After removal of the cooling bath,the reaction mixture was stirred at room temperature for 2 hours.Subsequently, the mixture was poured on to ice and extracted with ether.The organic phase was washed with water, dried and evaporated. Afterfiltration of the crude product over a short column (silica gel, elutingagent hexane/ethyl acetate=9:1) and crystallization from hexane, therewere obtained 5 g of 1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinylmethyl ketone in the form of slightly yellowish crystals, m.p. 46°-48°C.

EXAMPLE 6

In analogy to Example 5, from 6.5 g of 6-acetyl-1,4-benzodioxane and16.4 g of diethyl 4-carbethoxybenzyl)phosphonate, there were obtained,after filtration of the crude product over a column (silica gel, elutingagent hexane/ethyl acetate=9:1) and recrystallization from hexane/ethylacetate, 7.3 g of ethyl p-[(E)-2-(1,4-benzodioxan-6-yl)propenyl]benzoatein the form of colorless crystals, m.p. 64°-66° C.

In analogy to Example 2, by hydrolysis of the thus-obtained ester, therewas obtained p-[(E)-2-(1,4-benzodioxan-6-yl)propenyl]benzoic acid in theform of white crystals, m.p. 172°-173° C. (from ethyl acetate).

EXAMPLE 7

In analogy to Example 5, from 3.2 g of 6-acetyl-1,4-benzodithiane and7.4 g of diethyl 4-carbethoxybenzyl)phosphonate there were obtained,after filtration of the crude product over a column (silica gel,hexane/ethyl acetate=4:1) and recrystallization from hexane/ethylacetate, 3.1 g of ethylp-[(E)-2-(1,4-benzodithian-6-yl)propenyl]benzoate in the form ofcolorless crystals, m.p. 90°-92° C.

In analogy to Example 2, by hydrolysis of the thus-obtained ester withpotassium hydroxide and recrystallization from ethyl acetate/hexanethere is obtained p-[(E)-2-(1,4-benzodithian-6-yl)propenyl]benzoic acidin the form of white crystals, m.p. 236°-237° C.

EXAMPLE 8

15.1 g of α,2,2-trimethyl-1,3-benzodioxol-5-methanol were dissolved in450 ml of acetonitrile and stirred at 50° C. for 3.5 hours with 24.6 gof triphenylphosphine hydrobromide. Thereafter, the mixture wasevaporated in a vacuum. The residue was partitioned between 80 percentethanol and hexane (in each case 600 ml three times); theaqueous-ethanol phase was evaporated in a vacuum, taken up indichloromethane, dried over sodium sulfate, evaporated and dried in avacuum: 39.6 g of[α-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl]triphenylphosphonium bromideas a beige foam which did not crystallize, but which was practicallypure according to thin-layer chromatography (CH₂ Cl₂ +5% MeOH).

12.5 g of this phosphonium salt and 4.7 g of methyl 4-formylbenzoatewere boiled under reflux in 80 ml of 1,2-butylene oxide under argon for16 hours. After cooling the product was partitioned between hexane (300ml three times) and 70 percent ethanol (150 ml three times). Theaqueous-ethanol phases were subsequently extracted three times withhexane and 10% ethyl acetate. After evaporation, there were obtained5.46 g of hexane extract (A) and 1.23 g of hexane-ethyl acetate extract(B). Extract A yielded from hexane 2.39 g of crystalline, pure methylp-[(E)-2-(2,2-dimethyl-1,3-benzodioxol-5-yl) propenyl]-benzoate, m.p.72°-74° C. The mother liquors from extract A and extract B werechromatographed together on silica gel with hexane +5% ethyl acetate,whereby an additional 0.7 g of product of melting point 73°-75° C. wasobtained.

EXAMPLE 9

A. 24.2 g of ethyl α-(diethoxyphosphinyl)-p-toluate were added underargon and while cooling with ice to 3.87 g of sodium hydride (50% inmineral oil) in 50 ml of dimethylformamide. The mixture was stirred atroom temperature until the evolution of hydrogen had stopped.Thereafter, there was slowly added dropwise with ice/methanol cooling asolution of 15 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-ylmethyl ketone in 50 ml of dimethylformamide, whereby the internaltemperature rose to 35° C. After an additional half hour, the reactionmixture was added to ice/sodium chloride and extracted with ether. Theethereal solution was washed with water, dried over sodium sulfate andevaporated under reduced pressure. Chromatography on silica gel(petroleum ether/ethyl acetate: 97/3) yielded 16.2 g of crude productwhich, after recrystallization from hexane, yielded 12.6 g of ethylp[(E)-2-(3,4-dihydro-3,3,-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]benzoatein the form of pale yellow crystals. M.p. 99° C.

The starting material was prepared as follows:

B. 15 g of dimercaptobenzene were slowly added dropwise while cooling to5.55 g of sodium hydride (50% in mineral oil) in 150 ml of dimethylsulfoxide, whereby the internal temperature was held between 15° and 23°C. Subsequently, the reaction mixture was stirred at room temperaturefor 1 hour and cooled with ice/methanol. Thereafter, 50 g of2,2-dimethylpropanediol ditosylate in solid form were added in oneportion and the reaction mixture was heated to 80° C. for 3 hours.Thereafter, the reaction mixture was cooled, poured on to ice, extractedwith ether, the extract was washed with water and dried. Afterevaporation of the solvent, there was obtained a yellow oil which waschromatographed on silica gel (petroleum ether/ethyl acetate 99:1).There were obtained 14 g of3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine as a colorless oil.

C. 13.3 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine weredissolved in 110 ml of ethylene chloride under argon and treatedportionwise at -10° C. in succession with 10.1 ml of acetyl chloride and19 g of aluminum chloride. Thereafter, the reaction mixture was stirredat room temperature for 21/2 hours, poured on to ice and extracted withether. The extract was washed with dilute sodium hydroxide solution andwater, dried and evaporated to dryness. There were obtained 15.6 g of3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl methyl ketone in theform of brownish crystals.

EXAMPLE 10

In analogy to Example 9, from3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl methyl ketone therewas obtained ethylp-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]benzoate,m.p. 50°-51° C. The starting material was prepared in analogy to Example9, paragraphs B and C, starting from pyrocatechol via3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine.

EXAMPLE 11

In analogy to Example 9, from3,4-dihydro-3-methyl-2H-1,5-benzodithiepin-7-yl methyl ketone, there wasobtained ethylp-[(E)-2-(3,4-dihydro-3-methyl-2H-1,5-benzodithiepin-7-yl)propenyl]benzoate,m.p. 68°-70° C. The starting material was prepared in analogy to Example9, paragraphs B and C, via 3,4-dihydro-3-methyl-2H-1,5-benzodithiepine.

EXAMPLE 12

In analogy to Example 9, from 3,4-dihydro-2H-1,5-benzodithiepin-7-ylmethyl ketone, there was obtained ethylp-[(E)-2-(3,4-dihydro-2H-1,5-benzodithiepin-7-ylpropenyl]benzoate, m.p.98°-99° C. The starting material was prepared in analogy to Example 9,paragraphs B and C, via 3,4-dihydro-2H-1,5-benzodithiepine.

EXAMPLE 13

A. 4.9 g of 2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-8-methanol weredissolved in 50 ml of acetonitrile and treated with 13 g oftriphenylphosphine hydrobromide. The reaction mixture was stirred at 40°C. for 24 hours. Thereafter, the majority of the solvent was removedunder reduced pressure and the residue was partitioned between hexaneand ethanol/water (8:2). The heavy phase was evaporated and dried,whereby 11.96 g of white phosphonium salt were obtained. 6.29 g ofPhosphonium salt were dissolved in 13 ml of butylene oxide, treated with2.6 g of ethyl 4-formylbenzoate and heated to reflux for 18 hours.Thereafter, the majority of the solvent was removed under reducedpressure and the residue was partitioned between hexane andethanol/water (8:2). The light phase was dried over magnesium sulfateand evaporated. Chromatography on silica gel (petroleum ether/ethylacetate (97:3)) and recrystallization from hexane yielded 1.4 g of ethylp-[(E)-2-(2,3,4,5-tetrahydro-1-benzoxepin-8-yl)propenyl]benzoate, m.p.71°-72° C.

The starting material was prepared as follows:

m-Bromophenol was reacted with γ-butyrolactone in analogy to Example 17,paragraphs B, C and D, to give 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine.

B. 7.3 g of 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine in 30 ml ofabsolute tetrahydrofuran were added under argon to 930 mg of Mg shavingsand a granule of iodine. The reaction was initiated by the addition of afew drops of 1,2-dibromoethane and had finished after 2 hours.Thereafter, the reaction mixture was cooled to -10° C. and excessacetaldehyde was distilled into the reaction vessel. After 10 minutes,the mixture was hydrolyzed with saturated sodium bicarbonate (NaHCO₃ )solution, extracted with ether, washed with water, dried and evaporatedto dryness. Chromatography on silica gel (petroleum ether/ethyl acetate3:1) yielded 4.93 g of2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-8-methanol as a colorless oil.

EXAMPLE 14

In analogy to Example 13, from2,3,4,5-tetrahydro-α-methyl-3,3-dimethyl-2H-1-benzothiepine-8-methanolthere was obtained methylp-[(E)-2-(2,3,4,5-tetrahydro-3,3-dimethyl-2H-1-benzothiepin-8-yl)propenyl]benzoate,m.p. 82°-84° C. The starting material was prepared in analogy to Example13, paragraph B, from 8-bromo-2,3,4,5-tetrahydro-1-benzothiepine.

EXAMPLE 15

In analogy to Example 13, from2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-7-methanol, there was obtainedethyl p-[(E)-2-(2,3,4,5-tetrahydro-1-benzoxepin-7-yl)propenyl]benzoate,m.p. 60°-61° C. The starting material was prepared as follows:

6.90 g of 2,3,4,5-tetrahydro-1-benzoxepin-7-yl methyl ketone in 60 ml ofmethanol were treated portionwise with 2.33 g of sodium borohydride(NaBH₄) at 0° C. while stirring. After a half hour the reaction mixturewas poured on to ice, extracted with ether. The extract was washed withwater, dried and evaporated. Chromatography on silica gel (petroleumether/ethyl acetate 8:2) yielded 5.71 g of2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-7-methanol as a colorless oil.

The 2,3,4,5-tetrahydro-1-benzoxepin-7-yl methyl ketone can be obtainedin analogy to Example 18, paragraph B, from2,3,4,5-tetrahydro-1-benzoxepine by Friedel-Crafts reaction.

EXAMPLE 16

8.85 g of ethyl α-(diethoxyphosphinyl)-p-toluate were slowly addeddropwise to 1.3 g of sodium hydride (50% in mineral oil) in 28 ml ofdimethylformamide. The reaction mixture was stirred at room temperatureuntil the evolution of hydrogen had finished. Thereafter, 4.2 g of2,3,4,5-tetrahydro-3,3-dimethyl-benzothiepin-7-yl methyl ketone wereadded and the reaction mixture was stirred at room temperature for 2hours. Thereafter, the mixture was poured on to ice/sodium chloride,extracted with ether, the ethereal solution was washed with water anddried and evaporated. Chromatography on silica gel (petroleumether/ethyl acetate (95:5)) and recrystallization from hexane yieldedethylp-[(E)-2-(2,3,4,5-tetrahydro-3,3-dimethyl-1-benzothiepin-7-yl)propenyl]benzoateof melting point 96°-97° C.

The starting material was prepared as follows:

17.8 g of 3,3-Dimethylglutaric anhydride were heated to reflux overnightin 130 ml of absolute ethanol. The reaction solution was brought todryness (high vacuum), dissolved in 625 ml of benzene and stirred atroom temperature for 2 hours with 2.1 ml of dimethylformamide and 6.25ml of oxaxyl chloride. Thereafter, the reaction mixture is evaporatedunder reduced pressure. The thus-obtained acid chloride is dissolved in80 ml of cyclohexane and added dropwise to a solution, boiling underreflux, of 20.4 g of 2-mercaptopyridine 1-oxide Na, 1.4 g ofdimethylaminopyridine, 53.7 g of iodo form and 620 ml of cyclohexene.After 3 hours, the mixture is cooled, filtered and evaporated. Afterchromatography on silica gel (petroleum ether/ethyl acetate 9:1), therewere obtained 14.8 g of ethyl 4-iodo-3,3-dimethylbutyrate. Reaction ofthis compound with sodium thiophenolate followed by hydrolysis yielded4-phenylmercapto-3,3-dimethylbutyric acid which was converted via theacid chloride into 3,4-dihydro-3,3-dimethyl-1-benzothiepin-5(2H)-one.Reduction of the ketone in analogy to Example 17, paragraph D, andacetylation in analogy to Example 9, paragraph C. yielded2,3,4,5-tetrahydro-3,3-dimethyl-1-benzothiepin-7-yl methyl ketone.

EXAMPLE 17

A. In analogy to Example 16, from 2,3,4,5-tetrahydro-1-benzothiepin-8-ylmethyl ketone, there was obtained ethylp-[(E)-2-(2,3,4,5-tetrahydro-1-benzothiepin-8-yl)propenyl]benzoate, m.p.63°-64° C.

The starting material was prepared as follows:

B. 3.74 g of sodium were dissolved in 77 ml of absolute ethanol underargon. The solution was treated dropwise with 25 g of m-bromothiophenoland heated to reflux. Thereafter, 12.4 ml of γ-butyrolactone were addedand the reaction mixture was heated to 110° C. for 5 hours. Theseparated carboxylic acid sodium salt was removed by filtration, washedwith a small amount of ether and dissolved in 300 ml of water. Thesolution was acidified to pH 2 with 1N HCl while cooling with ice, thefree carboxylic acid was extracted with ether, the ethereal solution wasdried and evaporated. There were obtained 33.1 g of4-(m-bromophenylmercapto)butyric acid.

C. 33.1 g of the thus-obtained acid were heated to 120° C. with 275 g ofpolyphosphoric acid and 550 ml of o-xylene for 24 hours while stirringintensively. After cooling, the mixture was hydrolyzed with ice, dilutedwith water and extracted with ether. The organic phase was washed withwater, dried and evaporated. Chromatography on silica gel (petroleumether/ethyl acetate 9:1) yielded 22.1 g of8-bromo-3,4-dihydro-1-benzothiepin-5(2H)-one as a brownish oil.

D. 15.6 g of 8-bromo-3,4-dihydro-1-benzothiepin-5(2H)-one were dissolvedin 70 ml of diethylene glycol. The solution was treated with 6.55 ml ofhydrazine hydrate and 7.5 g of solid potassium hydroxide and heated to180°-190° C. under reflux for about 30 hours. After cooling, the mixturewas poured on to ice and extracted with ether. The organic phase waswashed with water, dried and evaporated. Chromatography on silica gelwith petroleum ether yielded is 10.7 g of8-bromo-2,3,4,5-tetrahydro-1-benzothiepine as a colorless oil.

E. The previously obtained bromide was converted into2,3,4,5-tetrahydro-α-methyl-1-benzothiepine-8-methanol by a Grignardreaction in analogy to Example 13, last paragraph.

F. 7.80 g of 2,3,4,5-tetrahydro-α-methyl-1-benzothiepine-8-methanol weredissolved in 100 ml of methylene chloride, treated with 50 g ofmanganese dioxide (MnO₂) and the reaction mixture was stirred overnight.Thereafter, the mixture was filtered over a filter aid and the solutionwas evaporated. There were obtained 7.30 g of2,3,4,5-tetrahydro-1-benzothiepin-8-yl methyl ketone as a colorless oil.

EXAMPLE 18

A. In analogy to Example 16, from2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-7-yl methyl ketone, there wasobtained ethylp-[(E)-2-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-7-yl)propenyl]benzoate,m.p. 65° C. The starting material was prepared as follows:

B. 3.32 g of 2,3,4,5-tetrahydro-5-methyl-1-benzothiepine were added at0° C. under argon to a solution of 2.64 ml of acetyl chloride and 4.96 gof aluminum chloride (AlCl₃) in 80 ml of ethylene chloride. The reactionmixture was stirred at room temperature overnight. Thereafter, it waspoured on to ice, and extracted with ether. The organic phase was washedwith 1N sodium hydroxide solution and water, dried and evaporated. Therewere obtained 3.66 g of 2,3,4,5-tetrahydr-5-methyl-1-benzothiepin-7-ylmethyl ketone as a brownish oil.

EXAMPLE 19

In analogy to Example 16, from 2,3,4,5-tetrahydro-1-benzothiepin-7-ylmethyl ketone, there was obtained ethylp-[(E)-2-(2,3,4,5-tetrahydro-1-benzothiepin-7-yl)propenyl]benzoate, m.p.98°-101° C. The starting material was prepared as follows:

3,4-Dihydro-1-benzothiepine (prepared from thiophenol in analogy toExample 17, paragraphs B and C) was converted analogously to Example 17,paragraph D, into 2,3,4,5-tetrahydro-1-benzothiepine from which the2,3,4,5-tetrahydro-1-benzothiepin-7-yl methyl ketone was obtained byFriedel-Crafts reaction in analogy to Example 18, paragraph B.

EXAMPLE 20

In analogy to Example 16, from2,3,4,5-tetrahydro-5,5-dimethyl-1-benzothiepin-7-yl methyl ketone, therewas obtained ethylp-[(E)-2-(2,3,4,5-tetrahydro-5,5-dimethyl-1-benzothiepin-7-yl)propenyl]benzoate,m.p. 65°-66° C. The starting material was prepared as follows:

A solution of 20.0 g of methoxymethyltriphenylphosphonium chloride in 60ml of absolute tetrahydrofuran was treated dropwise at 0° C. under argonwith 43 ml of 1.4N n-butyllithium in hexane. The mixture was stirred for1/4 hour. Thereafter, the mixture was treated with 8.02 g of3,4-dihydro-1-benzothiepin-5(2H)-one in a small amount oftetrahydrofuran. After 5 minutes, the cooling bath was removed and thereaction mixture was stirred at room temperature for an additional 11/2hours. Thereafter, the reaction mixture was partitioned betweenpetroleum ether and ethanol/water (8:2). The lighter phase was washedwith water, dried over sodium sulfate and evaporated. There wereobtained 11.8 g of crude product which were dissolved in 80 ml oftetrahydrofuran and treated under argon with 100 ml of 35% perchloricacid. The reaction mixture was stirred overnight, poured on to ice,extracted with ether, washed with 5% sodium carbonate solution, driedand evaporated. Chromatography on silica gel (petroleum ether/ethylacetate 92:8) yielded 5.04 g of2,3,4,5-tetrahydro-1-benzothiepine-5-carboxaldehyde as a colorless oil.

The thus-obtained product was dissolved in 50 ml of tert.-butanol andtreated under argon with 3.37 g of potassium tert.-butylate. After 10minutes at room temperature, the reaction solution was cooled to 0° C.and treated with 2.17 ml of methyl iodide. Thereafter, the reactionmixture was stirred at room temperature for 3 hours, poured on to ice,extracted with ether, washed with saturated sodium chloride solution anddried. After evaporation of the solvent and chromatography on silica gel(petroleum ether/ethyl acetate 92:8), there were obtained 3.29 g of2,3,4,5-tetrahydro-5-methyl-1-benzothiepine-5-carboxaldehyde.

The thus-obtained product was dissolved in 20 ml of diethylene glycoland treated with 1.67 ml of hydrazine hydrate and 2.81 g of potassiumhydroxide. The reaction mixture was heated slowly to 120° C., held atthis temperature for a half hour and then heated to 180° C. After 3hours, the mixture was cooled, partitioned between petroleum ether andwater and the organic phase was washed with water. After drying andevaporation to dryness and chromatography (petroleum ether), there wereobtained 2.4 g of 2,3,4,5-tetrahydro-5,5-dimethyl-1-benzothiepine as acolorless oil.

The thus-obtained product was converted into the2,3,4,5-tetrahydro-5,5-dimethyl-1-benzothiepin-7-yl methyl ketone by aFriedel-Crafts reaction in analogy to Example 18, paragraph B.

EXAMPLE 21

4.0 g of ethylp-[(E)-2-(2,3,4,5-tetrahydro-1-benzothiepin-7-yl)propenyl]benzoate in 30ml of methylene chloride were treated with 6.05 g of m-chloroperbenzoicacid (85%) and held at about +5° C. for 24 hours. Thereafter, themixture was diluted with methylene chloride, washed with bisulfitesolution and sodium carbonate solution, dried and evaporated.Recrystallization from ethyl acetate/hexane yielded 3.7 g of ethylp-[(E)-2-(2',3',4',5'-tetrahydro-1-benzothiepin-7'-yl)propenyl]benzoate1',1'-dioxide as pale yellow crystals of melting point 147°-148° C.

In analogy, there were prepared:

Ethylp-[(E)-2-(2',3',4',5'-tetrahydro-1-benzothiepin-8'-yl)propenyl]benzoate1',1'-dioxide, m.p. 117°-119° C.,

ethylp-[(E)-2-(2',3',4',5'-tetrahydro-5',5'-dimethyl-1-benzothiepin-7'-yl)propenyl]benzoate1',1'-dioxide, m.p. 142°-143° C.

ethylp-[(E)-2-(2',3',4',5'-tetrahydro-3',3'-dimethyl-1-benzothiepin-7'-yl)propenyl]benzoate1',1'-dioxide, m.p. 155°-156° C.

ethylp-[(E)-2-(3',4'-dihydro-3',3'-dimethyl-2'-H-1,5-benzodithiepin-7'-yl)propenyl]benzoate1',1',5',5'-tetroxide, m.p. 175°-176° C.

EXAMPLE 22

A solution of 4.47 g of2,3,4,5-tetrahydro-α-methyl-1-methyl-1H-1-benzazepine-7-methanol in 50ml of acetonitrile was treated with 9.73 g of triphenylphosphinehydrobromide. The reaction mixture was stirred at 30° C. for 20 hours,concentrated and the residue was partitioned between hexane and aqueousethanol (8:2). The lower phase was evaporated. The product was taken upin methylene chloride. The solution was dried and evaporated, whereby12.3 g of phosphonium salt were obtained in the form of reddishcrystals. 10.7 g of Phosphonium salt were suspended in 40 ml of absolutetetrahydrofuran under argon and deprotonized at 0° C. with 20.7 ml of1.4M n-butyllithium solution. After 15 minutes, the dark red solutionwas treated with 4.76 g of methyl 4-formylbenzoate and stirred at roomtemperature for 11/2 hours. Thereafter, the mixture was poured on toice, extracted with ether, washed with water and dried and evaporated.Chromatography on silica gel (petroleum ether/ethyl acetate (95:5 ) andrecrystallization from hexane/ethyl acetate yielded 3.6 g of methylp-[(E)-2-(2,3,4,5-tetrahydro-1-methyl-1-benzazepin-7-yl)propenyl]benzoatein the form of pale yellow crystals of melting point 106° C.

The starting material was prepared as follows:

A. 45 ml of dimethylformamide were treated under an argon atmospherewith 16.2 ml of phosphorus oxychloride. After the reaction had fadedaway, 7.30 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine were addedand the reaction mixture was stirred at 70° C. for 5 hours. Thereafter,the mixture was poured on to ice, made alkaline with sodium hydroxidesolution, extracted with ether, washed with water, dried and evaporated.Chromatography on silica gel (petroleum ether/ethyl acetate (87:13))yielded 4.38 g of2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine-7-carboxaldehyde.

The Grignard reagent was prepared from 1.04 g of magnesium shavings and2.30 ml of methyl iodide under argon in 40 ml of absolute ether. To thisGrignard solution was slowly added dropwise at room temperature asolution of 4.38 g of2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine-7-carboxaldehyde in 10 mlof ether. The reaction mixture was stirred for 2 hours. Thereafter, themixture was hydrolyzed with saturated ammonium chloride solution,extracted with ether, washed with water and dried. After evaporation,there were obtained 4.47 g of2,3,4,5-tetrahydro-α-methyl-1-methyl-1H-1-benzazepine-7-methanol as ayellow oil.

EXAMPLE 23

A solution of 1.2 g of ethylp-[(E)-2-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-7-yl)propenyl]benzoatein 30 ml of ethanol was treated with 5 ml of water which contained 0.8 gof sodium hyohoxide (NaOH). The reaction mixture was stirred at 35° C.overnight, poured on to ice, acidified with HCl and extracted withether. The organic phase was washed with water, dried and concentrated.After recrystallization from ethyl acetate, there were obtained 885 mgofp-[(E)-2-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-7-yl)-ropenyl]benzoicacid in the form of white crystals of melting point 186° C.

In an analogous manner, there were prepared:

p-[(E)-2-(3,4-Dihydro-3-methyl-2H-1,5-benzodithiepin-7-yl)propenyl]benzoicacid, m.p. 188°-189° C.

p-[(E)-2-(2',3',4',5'-tetrahydro-3',3'-dimethyl-1-benzothiepin-7'-yl)propenyl]benzoicacid 1',1'-dioxide, m.p. 250°-253° C.

p-[(E)-2-(2',3',4',5'-tetrahydro-1-benzothiepin-7'-yl)propenyl]benzoicacid 1',1'-dioxide, m.p. 240°-241° C.,

P-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7'-yl)propenyl]benzoicacid, m.p. 212°-213° C.,

p-[(E)-2-(2',3',4',5'-tetrahydro-5',5'-dimethyl-1-benzothiepin-7'-yl)propenyl]benzoicacid 1',1'-dioxide, m.p. 225°-226° C.

p-[(E)-2-(2',3',4',5'-tetrahydro-1-benzothiepin-8'-yl)propenyl]benzoicacid 1',1'-dioxide, m.p. 219°-220° C.,

p-[(E)-2-(2,3,4,5-tetrahydro-1-benzothiepin-7-yl)propenyl]benzoic acid,m.p. 217°-218° C.

p-[(E)-2-(2,3,4,5-tetrahydro-5,5-dimethyl-1-benzothiepin-7-yl)propenyl]benzoicacid, m.p. 178°-179° C.,

p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]benzoicacid, m.p. 198°-199° C.,

p-[(E)-2-(2,3,4,5-tetrahydro-1-benzothiepin-8-yl)propenyl]benzoic acid,m.p. 217°-218° C.

EXAMPLE 24

In analogy to Example 22, from3,4-dihydro-α3,3-trimethyl-2H-1,5-benzodithiepin-7-ylmethanol, there wasprepared methylp-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]benzoate,m.p. 142°-143° C. The starting material was synthesized from3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl methyl ketone,prepared in Example 9(C), by reduction with sodium borohydride.

EXAMPLE 25

In analogy to Example 13 (paragraphs A and C), but using methyl4-formylbenzoate in place of ethyl 4-formylbenzoate as the carbonylcomponent, there was prepared methylp-[(E)-2-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-8-yl)propenyl]benzoate,m.p. 88°-89° C.

The starting material was prepared as follows:

First, m-bromothiophenol was converted into8-bromo3,4-dihydro-1-benzothiepin-5(2H)-one. This ketone was methylatedwith MeMgI in ether and the resulting tertiary alcohol was deoxygenatedas follows: 22.85 g were placed in 250 ml of hexane under argon andtreated in succession with 75.1 g of sodium iodide (NaI), 26.4 ml ofacetonitrile and 63.5 ml of Me₃ SiCl. The mixture was stirred at roomtemperature overnight, poured on to ice, extracted with ether, washedwith bisulfite solution and water, dried and evaporated. Chromatographyon silica gel with petroleum ether gave 18.1 g of8-bromo-2,3,4,5-tetrahydro-5-methyl-1-benzothiepine as a pale yellowoil.

EXAMPLE 26

In analogy to Example 9 (paragraphs A and C), from2,3,4,5-tetrahydro-3-methyl-1-benzothiepine, there was prepared ethylp-[(E)-2-(2,3,4,5-tetrahydro-3-methyl-1-tienzothiepin-7-yl)propenyl]benzoate,m.p. 46°-49° C.

The starting material was prepared as follows:

Thiophenol was alkylated with 1-bromo-3-chloro-2-methylpropane in thepresence of potassium carbonate (K₂ CO₃) in acetone. The resultingprimary chloride was lengthened by one carbon atom using KCN/18-crown-6in acetonitrile. Basic hydrolysis, ring closure with polyphosphoric acidin analogy to Example 17(C) and Wolf-Kishner reduction according toExample 17(D) finally gave the required2,3,4,5-tetrahydro-3-methyl-1-benzothiepine as a colorless oil.

EXAMPLE 27

In analogy to Example 20, from3,4-dihydro-3-methyl-1-benzothiepin-5(2H)-one, there was prepared ethylp-[(E)-2-(2,3,4,5-tetrahydro-3,5,5-trimethyl-2H-1-benzothiepin-7-yl)propenyl]benzoate,m.p. 99°-100° C.

EXAMPLE 28

In analogy to Example 16, from2,3-dihydro-3,3-dimethyl-1,4-benzoxathiin-7-yl methyl ketone, there wasprepared ethylp-[(E)-2-(2,3-dihydro-3,3-dimethyl-1,4-benzoxathiin-7-yl)propenyl]benzoate,m.p. 69°-70° C.

The starting material was prepared as follows:

4.11 ml of 2-mercaptophenol and 27.4 g of finely powdered K₂ CO₃ wereplaced in 40 ml of dimethyl formamide (DMF) and treated at 0° C. underan argon atmosphere with 4.08 ml of β-methallyl chloride. The mixturewas left to react at room temperature for 1/2 hour, poured on to ice andextracted with ether. After washing with water, drying and evaporationthere were obtained 7.80 g of a pale yellow oil which was dissolved in60 ml of chloroform and, after the addition of 1 g of p-toluenesulfonicacid, heated to reflux overnight. Extractive working-up (ether) gave6.96 g of tlc-uniform 2,3-dihydro-3,3-dimethyl-1,4-benzoxathien as acolorless oil. This was regioselectively acetylated in analogy toExample 18(B) to give 2,3-dihydro-3,3-dimethyl-1,4-benzoxathien-7-ylmethyl ketone.

EXAMPLE 29

In analogy to Example 22, from2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-1H-1,5-benzodiazepine, there wasprepared methylp-[(E)-2-(2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-1H-1,5-benzodiazepin-7-yl)propenyl]benzoate,m.p. 120°-121° C.

The starting material was prepared as follows:

120 mmol of NANH₂ (50% suspension in toluene) were placed in 40 ml ofabsolute tetrohydrofuran (THF) under argon. 40 mmol of t-BuOH in 10 mlof THF were added thereto and the mixture was stirred at 50° C. for 2hours. Then, 40 mmol (5.2 g) of 1,3-diamino-N,N,2,2-tetramethylpropane,dissolved in 20 ml of THF, were added dropwise and the mixture wasstirred at 50° C. for an additional hour. The mixture was cooled to 30°C., diluted with 200 ml of THF and 40 mmol (4.6 ml) of1,2-dichlorobenzene were added thereto. After 18 hours, the mixture wasworked-up extractively (ether). Rapid chromatography of the crudeproduct on silica gel with hexane yielded 4.4 g of red-brown crystals.

EXAMPLE 30

4.2 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine-7-carboxylicacid were treated with 3 ml of SOCl₂ and heated under reflux for 1 hour.The excess reagent was evaporated in a vacuum and the resulting acidchloride was dried in a high vacuum. It was then dissolved in 70 ml ofpyridine and there was slowly added dropwise thereto at 0° C. under anArgon atmosphere a solution of 4.05 g of ethyl p-aminobenzoate in 70 mlof pyridine. The mixture was left to react at room temperature for 2hours, concentrated to 1/4 of the volume and partitioned between etherand dilute HCl. The organic phase was washed thoroughly with water,dried and concentrated. The product thereby crystallized out. Aftercooling, suction filtration and drying, there were obtained 5.9 g ofethylp-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine-7-carboxamido)benzoateas colorless crystals of m.p. 181°-182° C.

The starting material was prepared as follows:

A. 8.55 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine (see Example10) were dissolved in 70 ml of methylene chloride (CH₂ Cl₂) and treatedat 0° C. under an Argon atmosphere with a solution of 8.0 g of Br₂ in 30ml of CH₂ Cl₂. The mixture was warmed to room temperature and left toreact for 1 hour. It was then poured on to ice and extracted with ether.Washing with NaHCO₃ solution and water, drying and evaporation yielded13.35 g of 7-bromo-3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine as acolorless oil which was 94.5% pure and which contained 4.7% of startingmaterial; it was processed in the crude state.

B. The Grignard compound was prepared from 6.0 g of the thus-obtainedbromide and 675 mg of Mg shavings under an Argon atmosphere in 25 ml ofTHF. The metallization had finished after 3 hours. The mixture wascooled to -10° C. and a vigorous stream of CO₂ was conducted in over 30minutes. Ice was added cautiously thereto. The mixture was partitionedbetween dil. NaOH and ether, and the aqueous phase was adjusted to pH 1with HCl and again extracted with ether. Washing with water, drying andevaporation yielded 4.2 g of3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine-7-carboxylic acid ascolorless crystals of m.p. 172°-173° C.

EXAMPLE 31

In analogy to Example 30, from3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine-7-carboxylic acidchloride, there was prepared ethylp-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine-7-carboxamido)benzoate,m.p. 180°-181° C.

The starting material was prepared in analogy to Example 30, paragraphsA and B, with Fe powder being used as the catalyst in the brominationand the acid chloride being prepared from the acid with oxalyl chloride.

EXAMPLE 32

In analogy to Example 30, from2,3,4,5-tetrahydro-5-methyl-1-benzothiepine-8-carboxylic acid chloride,there was prepared ethylp-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepine-8-carboxamido)benzoate,m.p. 132°-133° C.

EXAMPLE 33

In analogy to Example 30, from2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid chloride, there wasprepared ethylp-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoate, m.p. 100°C.

EXAMPLE 34

In analogy to Example 30, from2,3,4,5-tetrahydro-1-benzothiepine-7-carboxylic acid chloride, there wasprepared ethylp-(2,3,4,5-tetrahydro-1-benzothiepine-7-carboxamido)benzoate, m.p. 145°C.

The starting material was prepared from7-bromo-2,3,4,5-tetrahydro-1-benzothiepine in analogy to the proceduredescribed in Example 30 and the latter compound was prepared startingfrom p-bromothiophenol in analogy to Example 17.

EXAMPLE 35

10.0 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl methylketone (see Example 9) were dissolved in 100 ml of EtOH and treatedportionwise with 2.0 g of NaBH₄. The mixture was left to react at roomtemperature overnight, and was diluted with water and extracted withether. Washing with water, drying and evaporation yielded 10.0 g ofsecondary alcohol which was further processed in the crude state.

The secondary alcohol was dissolved in 150 ml of acetonitrile andtreated with 19.5 g of triphenylphosphine hydrobromide. The mixture wasstirred at 40° C. overnight and the majority of the solvent was thenevaporated in a vacuum. The residue was partitioned between hexane andEtOH/H₂ O=8/2, the heavy phase was evaporated and the residue wasdissolved in CH₂ Cl₂. Drying and evaporation gave a foam which wasdigested during several hours in hexane/ether=2/1; 20.6 g of colorlesscrystals thereby resulted.

4.64 g of the foregoing crystals were placed in 25 ml of THF andconverted into the ylide at 0° C. with 5.8 ml of 1.6N nBuLi (hexane).The mixture was stirred at 0° C. for 1/4 hour and 1.90 g of undiluted4-(2-morpholinoethoxy)benzaldehyde were then added thereto. The mixturewas left to warm to room temperature and was worked-up as follows afteran additional 1 hour: the mixture was partitioned between EtOH/H₂ O=8/2and hexane/AcOEt=95/5 and the lighter phase was evaporated. Columnchromatography on silica gel (ethyl acetate) of the thus-obtained crudeproduct and crystallization from ether finally yielded 1.20 g of4-[2-[p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]phenoxy]ethyl]morpholinein the form of white crystals of m.p. 117°-118° C.

EXAMPLE 36

In analogy to Example 35, from3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl methyl ketone, therewas prepared4-[2-[p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]phenoxy]ethyl]morpholine,m.p. 104°-105° C.

EXAMPLE 37

In analogy to Example 36, but using p-ethoxycarbonyloxybenzaldehyde asthe carbonyl component, there was preparedp-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]phenylethyl carbonate.

590 mg of the foregoing carbonate were dissolved in 15 ml of ethanol andtreated with 7 ml of water containing 700 mg of NaOH pellets. Themixture was stirred at 50° C. overnight, poured on to ice, extractedwith ether, washed with water, dried and evaporated. Columnchromatography on silica gel (petroleum ether/ethyl acetate=85/15) andsubsequent crystallization from hexane/ether yielded 270 mg ofp-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]phenolas white crystals of m.p. 70°-71° C.

EXAMPLE 38

8.30 g of 3,4-dihydro-2H-1,5-benzothiazepine hydrobromide were placed in150 ml of THF and deprotonized with 48 ml of 1.55M nBuLi (hexane) underan Argon atmosphere at -10° C. After 1/4 hour, 4.64 ml of Methyl iodide(MeI) were added dropwise to the yellow solution of the Li amide and themixture was stirred for 1 hour. It was then poured on to ice, extractedwith ether, washed with water, dried and evaporated. Columnchromatography on silica gel (petroleum ether/ethyl acetate 96/4)yielded 5.70 g of 3,4-dihydro-5-methyl-2H-1,5-benzothiazepine as acolorless oil which was formulated as follows:

200 ml of DMF were placed under an Argon atmosphere and 11.3 ml ofphosphorus oxychloride (POCl₃) were added dropwise thereto whilecooling. The mixture was stirred at room temperature for 1/4 hour, 5.70g of the aromatic substrate were added thereto and the mixture washeated to 60°-70° C. for 1.5 hours. After cooling the mixture was pouredon to ice, extracted with ether, washed with water, dried andevaporated. Crystallization from hexane/ethyl acetate yielded 5.20 g ofaldehyde as yellow crystals of m.p. 56°-57° C. which was reacted asfollows:

80 ml of ether, in which 5.20 g of the foregoing aldehyde had beendissolved, were slowly added dropwise at room temperature under an Argonatmosphere to an ethereal MeMgI solution which had been prepared from968 mg of Mg shavings and 2.5 ml of MeI according to standardprocedures. The mixture was stirred at room temperature for anadditional 2 hours then hydrolyzed with ammonium chloride (NH₄ Cl)solution and extracted with ether. Washing with water, drying andremoval of the solvent in a vacuum yielded 5.50 g of secondary alcoholas an oil which was processed in the crude state.

The foregoing oil was placed in 40 ml of acetonitrile and treated with10.1 g of triphenylphosphine hydrobromide. The mixture was stirred at40° C. overnight and the clear solution was then concentrated in avacuum. The residue was partitioned between hexane and EtOH/H₂ O=8/2 andthe heavy phase was evaporated. The thus-obtained crude product wasdissolved in CH₂ Cl₂, dried over Sodium sulfate (Na₂ SO₄) andevaporated. Stirring for several hours in hexane/ether (2/1) finallyyielded 14.4 g of crystalline phosphonium salt.

These 14.4 g of phosphonium salt were placed in 60 ml of THF under anArgon atmosphere and converted into the deep red ylide at 0° C. with22.1 ml of 1.5M nBuLi (hexane). After 5 minutes, 4.65 g of methyl4-formyl-benzoate were added thereto as the solid and the cooling bathwas subsequently removed. After 1.5 hours, the mixture was poured on toice, extracted with ether, washed with water, dried and evaporated.Careful chromatography on silica gel (petroleum ether/ethyl acetate92/8) and recrystallization from hexane/ethyl acetate finally yielded2.65 g of methylp-[(E)-2-(3,4-dihydro-5-methyl-2H-1,5-benzothiazepin-8-yl)propenyl]benzoateas yellow crystals of m.p. 97°-98° C.

EXAMPLE 39

In analogy to Example 38, there was prepared methylp-[(E)-2-(3,4-dihydro-3,5-dimethyl-2H-1,5-benzothiazepin-8-yl)propenyl]benzoate,m.p. 101°-102° C.

The starting material was synthesized as follows:

18.8 g of 2-aminothiophenol were placed in 75 ml of acetone and treatedat 0° C. with 41.6 g of powdered K₂ CO₃ and 18.2 ml of1-bromo-3-chloro-2-methylpropane, whereby a strong exothermic reactionset in immediately. After 2 hours the mixture was poured on to ice,extracted with ether, washed with water, dried and evaporated. Therewere obtained 32.0 g of S-alkylated product which was dissolved in 80 mlof acetone. The solution was treated with 111 g of sodium iodide (NaI)and heated (oil bath 90° C.) for 3 days. The mixture was cooled, pouredon to ice, made basic with sodium hydroxide solution, extracted withether, washed with water, dried and evaporated. Column chromatography onsilica gel (petroleum ether/ethyl acetate 95/5) yielded 10.0 g of3,4-dihydro-3-methyl-2H-1,5-benzothiazepine as a colorless oil, althoughcontaminated with 14% of an unknown compound. A complete purificationwas carried out at the aldehyde stage.

The further reaction was effected as in Example 38 by formylation,reaction with methyl magnesium iodide and preparation of the phosphoniumsalt.

EXAMPLE 40

In analogy to Example 35, but using4-(2-dimethylaminoethoxy)benzaldehyde as the carbonyl component, therewas obtainedN,N-dimethyl-2-[p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]phenoxy]ethylamine,m.p. 46°-47° C.

EXAMPLE 41

In analogy to Example 30, from2,3,4,5-tetrahydro-3-methyl-1-benzothiepine-7-carboxylic acidchloride-1,1-dioxide, there was obtained ethylp-(2,3,4,5-tetrahydro-3-methyl-1-benzothiepine-7-carboxamido)benzoate1,1-dioxide, m.p. 181°-182° C.

The starting material was prepared as follows:

2,3,4,5-Tetrahydro-3-methyl-1-benzothiepin-7-yl methyl ketone wasoxidized in analogy to Example 21 to give the sulfone and this wassubjected to a hypochlorite degradation.

23.6 g of Ca(OCl)₂ were placed in 88 ml of water and treated with 16.6 gof K₂ CO₃ and 4.77 g of NaOH dissolved in 44 ml of water. The mixturewas stirred for 15 minutes. The precipitate was removed by filtrationand the filtrate was heated to 50° C. Thereafter, 11.4 g of2,3,4,5-tetrahydro-3-methyl-1-benzothiepin-7-yl methyl ketone1,1-dioxide were added, whereby the temperature rose to 90° C. as aconsequence of the heat of reaction. After 2 hours, the mixture wascooled, filtered and the filtrate was adjusted to pH 1 with 3N HCl whileflushing with Argon (evolution of Cl₂). The separated acid was removedby filtration under suction, washed with water and dried; yield 9.60 g,m.p. 209°-212° C.

EXAMPLE 42

In an analogous manner to Example 23, there were prepared:

p-[(E)-2-(2,3-Dihydro-3,3-dimethyl-1,4-benzoxathiin-7-yl)propenyl]benzoicacid, m.p. 217°-218° C.;

p-[(E)-2-(3,4-dihydro-2H-1,5-benzodithiepin-7-yl)propenyl]benzoic acid,m.p. 202°-203° C.;

p-[(E)-2-(2,3,4,5-tetrahydro-3-methyl-1-benzothiepin-7-yl)propenyl]benzoicacid, m.p. 195°-196° C.;

p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]benzoicacid, m.p. 198°-199° C.;

p-[(E)-2-(2,3,4,5-tetrahydro-5,5-dimethyl-1-benzothiepin-7-yl)propenyl]benzoicacid, m.p. 178°-179° C.;

p-[(E)-2-(3,4-dihydro-5-methyl-2H-1,5-benzothiazepin-8-yl)propenyl]benzoicacid, m.p. 197°-198° C.;p-[(E)-2-(2,3,4,5-tetrahydro-3,5,5-trimethyl-2H-1-benzothiepin-7-yl)propenyl]benzoicacid, m.p. 175°-176° C.; andp-[(E)-2-(3,4-dihydro-3,5-dimethyl-2H-1,5-benzothiazepin-8-yl)propenyl]benzoicacid, m.p. 213°-214° C.

EXAMPLE 43

1.20 g of ethylp-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoate weredissolved in 40 ml of ethanol and treated with 14 ml of water containing1.40 g of NaOH. The mixture was stirred at room temperature overnight,poured on to ice and acidified with conc. HCl. The mixture was thenextracted twice with ethyl acetate, washed with is water, dried andevaporated. Recrystallization from ethyl acetate gave 925 mg ofp-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoic acid ascolorless crystals of m.p. 261°-262° C.

EXAMPLE 44

28.9 g of aluminum chloride were added portionwise at 0° C. to 16.8 mlof acetyl chloride in 360 ml of methylene chloride. After an additional30 minutes at 0° C., a solution of 35.9 g of2,2-dimethyl-1,3-benzodithiol in 180 ml of methylene chloride was slowlyadded dropwise and the mixture was stirred at 0° C. for an additional 12hours and thereafter at 20° C. for 5 hours. Thereafter, the mixture waspoured on to ice, extracted with methylene chloride and the extractswere washed neutral with dilute sodium hydroxide solution and water,dried over sodium sulfate and evaporated. After recrystallization frommethanol/ water, there were obtained 41.8 g of2,2-dimethyl-1,3-benzodithiol-5-yl methyl ketone, melting point 75°-76°C. Then, 41.8 g of this ketone were dissolved in 1 l of ethanol, cooledto 0° C. and 7 g of sodium borohydride were added portionwise.Thereafter, the mixture was stirred at 20° C. for 3 hours, evaporated ina vacuum to a large extent, 200 ml of water were added, the mixture wasadjusted slowly to pH 4 with 1N sulfuric acid while cooling andextracted three times with ether. The extracts were washed with water,dried and evaporated, and 42.6 g ofα,2,2-trimethyl-1,3-benzodithiol-5-methanol were obtained. Thereafter,39.5 g of this alcohol were reacted with 65.9 g of triphenylphosphinehydrobromide in 500 ml of acetonitrile and worked-up as described inExample 8 and 96.3 g of[1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphoniumbromide were obtained. Then, 17.0 g of this phosphonium salt werereacted with methyl 4-formyl-benzoate in analogy to Example 8. Afterworking-up and recrystallization from ethyl acetate/hexane, there wereobtained 4.9 g of methylp-[(E)-2-(2,2-dimethyl-1,3-benzo-dithiol-5-yl)propenyl]benzoate in theform of colorless crystals, melting point 86°-87° C.

EXAMPLE 45

6.6 g of[1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphoniumbromide were dissolved in 40 ml of tetrahydrofuran and treated slowly at0° C. with 9 ml of a 1.5 molar solution of n-butyllithium in hexane.After 40 minutes, 3.5 g of 4-(2-morpholinoethoxy)benzaldehyde in 10 mlof tetrahydrofuran were added dropwise to the dark red solution and themixture was stirred at 20° C. for 16 hours. The mixture was then pouredon to ice and extracted with ethyl acetate. The combined extracts werewashed with water, dried and evaporated. After chromatography (silicagel, eluting agent ethyl acetate) and crystallization from ether/hexane,there were obtained 1.8 g of4-[2-[p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenoxy]ethyl]morpholinein the form of colorless crystals, melting point 90°-91° C.

EXAMPLE 46

In analogy to Example 45, by reacting[1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphoniumbromide with benzaldehyde, there was obtained2,2-dimethyl-5-[(E)-α-methylstyryl]-1,3-benzodithiol, melting point57°-58° C.

EXAMPLE 47

In analogy to Example 45, by reacting[1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphoniumbromide with ethyl 4-formylphenyl carbonate, there was obtained ethylp-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenyl carbonate,melting point 93°-94° C. Hydrolysis of this compound with aqueouspotassium hydroxide in ethanol gavep-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenol, meltingpoint 123°-124° C.

EXAMPLE 48

In analogy to Example 23, by hydrolyzing methylp-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]benzoate, therewas obtainedp-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]benzoic acid,melting point 204°-206° C.

EXAMPLE 49

16.5 g of [1-(4,4-dimethyl-6-chromanyl)ethyl]triphenylphosphoniumbromide and 3 g of benzaldehyde were heated under reflux in 100 ml ofbutylene oxide for 20 hours. The reaction mixture obtained was pouredinto a methanol/water mixture (6:4) and extracted with hexane. Afterdrying and evaporating the organic phase the crude product waschromatographed (silica gel, eluting agent hexane) and recrystallizedfrom hexane. There were obtained 1.5 g of3,4-dihydro-4,4-dimethyl-6-[(E)-α-methylstyryl]-2H-1-benzopyran in theform of colorless crystals, melting point 64°-65° C.

EXAMPLE 50

1.1 g of sodium hydride (50% suspension in mineral oil) were washedtwice with pentane, dried and suspended in 20 ml of dimethylformamide. Asolution of 10.9 g of[1-(4,4-dimethyl-6-thiochromanyl)ethyl]triphenylphosphonium bromide in60 ml of dimethylformamide was added dropwise thereto at 0° C. Afterstirring at 0° C. for 1 hour, a solution of 2.1 g of benzaldehyde in 20ml of dimethylformamide was added dropwise and the mixture was stirredat room temperature for an additional 3 hours. After working-up inanalogy to Example 49, the crude product was recrystallized from hexaneand gave 3.3 g of3,4-dihydro-4,4-dimethyl-6-(α-methylstyryl)-2H-1-benzothiopyran, meltingpoint 81°-83° C.

EXAMPLE 51

Oxidation of the compound obtained according to Example 50 withm-chloroperbenzoic acid in analogy to Example 4, gave3,4-dihydro-4,4-dimethyl-6-(α-methylstyryl)-2H-1-benzothiopyran1,1-dioxide, melting point 156°-158° C.

EXAMPLE 52

5.1 g of[1-(1,2,3,4-tetrahydro-1,4,4-trimethyl-6-quinolinyl)ethyl]triphenylphosphoniumbromide were suspended in 40 ml of tetrahydrofuran and treated at -20°C. with 5.9 ml of a 1.6 molar solution of n-butyllithium in hexane.After stirring at -20° C. for 1 hour, 1 g of benzaldehyde was addedthereto and the mixture was stirred at room temperature for anadditional 1 hour. After working-up in analogy to Example 49 andrecrystallization from hexane, there were obtained 1.2 g of1,2,3,4-tetrahydro-1,4,4-trimethyl-6-(α-methylstyryl)quinoline, meltingpoint 69°-71° C.

EXAMPLE 53

33 g of[1-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)ethyl]triphenylphosphoniumbromide and 6.5 g of benzaldehyde were heated under reflux in 300 ml ofbutylene oxide for 16 hours. After working-up in analogy to Example 49and recrystallization from hexane, there were obtained 7.9 g of3,4-dihydro-4,4-dimethyl-7-(α-methylstyryl)-2H-1-benzothiopyran, meltingpoint 67°-69° C.

EXAMPLE 54

Oxidation of the compound obtained according to Example 53 withm-chloroperbenzoic acid, in analogy to Example 4 gave3,4-dihydro-4,4-dimethyl-7-(α-methylstyryl)-2H-1-benzothiopyran1,1-dioxide, melting point 148°-150° C. (from ethyl acetate).

EXAMPLE 55

1.7 g of magnesium shavings were covered with 10 ml of ether. A solutionof 7.7 g of benzyl chloride in 80 ml of ether was added dropwise theretounder slight reflux and the mixture was subsequently held at boiling foran additional hour until the magnesium had dissolved completely. Aftercooling to room temperature, a solution of 7 g of3,4-dihydro-4,4-dimethyl-7-acetyl-2H-1-benzopyran in 50 ml of ether wasadded dropwise and the reaction mixture was heated under reflux for anadditional 2.5 hours. After cooling, the mixture was poured on to ice/2Nhydrochloric acid and extracted with ether. The organic phase was washedwith water and dilute sodium bicarbonate solution, dried and evaporated.The thus-obtained slightly yellow oil was dissolved in 10 ml of aceticacid and, after the addition of 0.5 g of p-toluenesulfonic acid, heatedunder reflux for 2 hours. The reaction solution obtained was dilutedwith water and extracted several times with ether. The combined extractswere diluted with water, washed with sodium bicarbonate solution andwater, dried and evaporated. The crude product was chromatographed(silica gel, eluting agent hexane/0.5% ethyl acetate) and recrystallizedfrom hexane. There were obtained 4.8 g of3,4-dihydro-4,4-dimethyl-7-(α-methylstyryl)-2H-1-benzopyran, meltingpoint 44°-46° C.

EXAMPLE 56

In analogy to Example 55, by a Grignard reaction of benzylmagnesiumchloride with 3,4-dihydro-1,4,4-trimethyl-7-acetylquinoline, there wasprepared 3,4-dihydro-1,4,4-trimethyl-7-(α-methylstyryl)quinoline,melting point 66°-68° C. (from hexane).

EXAMPLE 57

A solution of 14.2 g of 7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzopyranand 1.1 g of 1,2-dibromoethane in 80 ml of tetrahydrofuran was addeddropwise using a heatable ultrasonics bath, to a suspension, boilingunder reflux, of 1.6 g of magnesium shavings in 20 ml oftetrahydrofuran. After heating under reflux for an additional 2 hours,the reaction mixture was cooled to 0° C. and a strong stream of carbondioxide gas was conducted in (about 1 hour). Thereafter, the mixture waspoured on to ice, acidified with 2N hydrochloric acid and extracted withethyl acetate. The organic extracts were washed with water, dried andevaporated. After recrystallization from ethyl acetate/hexane, therewere obtained 5.3 g of3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-carboxylic acid, meltingpoint 173°-174° C.

1.4 g of the thus-obtained acid were heated under reflux for 1 hour with20 ml of thionyl chloride. The excess thionyl chloride was subsequentlydistilled off in a water-jet vacuum. The residual acid chloride wasdissolved in 20 ml of tetrahydrofuran and added dropwise at roomtemperature to a solution of 1.2 g of methyl 4-amino-benzoate in 30 mlof pyridine. After stirring for 1 hour, the mixture was poured on toice/water and extracted with ethyl acetate. The organic extracts werewashed twice with 2N hydrochloric acid and water, dried and evaporated.After filtration of the crude product over a silica gel column (elutingagent hexane/ethyl acetate 2:1), there were obtained 2.4 g of ethylp-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-carboxamido)benzoate as acolorless oil.

The ethyl ester was dissolved in 20 ml of ethanol and treated with asolution of 1.9 g of potassium hydroxide in 10 ml of water. Afterstirring at 40° C. for 1 hour, the mixture was poured on to ice,acidified with cold 2N hydrochloric acid and extracted with ethylacetate. The organic extracts were washed with water, dried andevaporated. After recrystallization of the crude product from ethylacetate/hexane, there were obtained 2.1 g ofp-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-carboxamido)benzoic acidin the form of colorless crystals, melting point 279°-281° C.

EXAMPLE 58

11 g of 7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran weredissolved in a mixture of 100 ml of ether and 10 ml of tetrahydrofuranand treated at -78° C. with 33 ml of a 1.6 molar solution ofn-butyllithium in hexane. The reaction solution was held at -50° C. for15 minutes, again cooled to -78° C. and gassed with carbon dioxide for 2hours. Thereafter, the mixture was poured on to ice, acidified with 6Nhydrochloric acid and extracted with ethyl acetate. The organic phaseswere washed with water, dried and evaporated. After recrystallization ofthe crude product from ethyl acetate/hexane, there were obtained 4.6 gof 3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxylic acid,melting point 202°-204° C.

5.4 g of this acid were treated with 30 ml of oxalyl chloride and heatedat reflux for 1 hour. After evaporation of the excess acid chloride, theresidue was dissolved in 50 ml of tetrahydrofuran and added dropwise atroom temperature to a solution of 3.6 g of ethyl 4-amino-benzoate and 70ml of pyridine. Working-up in analogy to Example 57 andrecrystallization from ethyl acetate/hexane gave 6.6 g of ethylp-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoatein the form of white crystals, melting point 148°-150° C.

Hydrolysis of the foregoing ester with potassium hydroxide/ethanol/waterin analogy to Example 57 gavep-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoicacid, melting point 274°-276° C.

EXAMPLE 59

Oxidation of 4 g of ethylp-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoatewith m-chloroperbenzoic acid in analogy to Example 4 gave, afterrecrystallization from ethyl acetate/hexane, 4.2 g of ethylp-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoate1,1-dioxide, melting point 208°-210° C. Hydrolysis of this compound inanalogy to Example 57, gavep-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoicacid 1,1-dioxide, melting point 314°-316° C.

EXAMPLE 60

2.7 g of 7-bromo-1,2,3,4-tetrahydro-1,4,4-trimethylquinoline weredissolved in 100 ml of ether and treated at -78° C. with 27 ml ofn-butyllithium (1.6 mol in hexane). After stirring at -40° C. for 3hours, carbon dioxide gas was conducted in during 1.5 hours. Theworking-up was effected in analogy to Example 57 and gave, afterrecrystallization from ethyl acetate/hexane, 1.9 g of1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinecarboxylic acid, meltingpoint 166°-168° C.

1.4 g of this acid were converted with oxalyl chloride in analogy toExample 58 into the acid chloride which was reacted with 1.1 g of ethyl4-amino-benzoate in 100 ml of pyridine to give 1.7 g of ethylp-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinecarboxamido)benzoate,melting point 118°-119° C. (from ether/hexane).

Hydrolysis of this ester with potassium hydroxide/water/ethanol gave,after recrystallization from ethyl acetate/hexane,p-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinecarboxamido)benzoicacid, melting point 279° C. (decomposition).

EXAMPLE 61

In analogy to Example 60, from7-bromo-1-decyl-1,2,3,4-tetrahydro-4,4-dimethylquinoline, there wasprepared ethylp-(1-decyl-1,2,3,4-tetrahydro-4,4-dimethyl-7-quinolinecarboxamido)benzoate,melting point 105°-106° C. (from ethyl acetate/hexane).

Hydrolysis of the ester in analogy to Example 57 yieldedp-(1-decyl-1,2,3,4-tetrahydro-4,4-dimethyl-7-quinolinecarboxamido)benzoicacid, melting point 194°-196° C. (from ethyl acetate/hexane).

EXAMPLE 62

3.7 g of 1,4-benzodioxane-6-carboxylic acid were treated with 50 ml ofthionyl chloride. After boiling at reflux for 1 hour, the excess thionylchloride was evaporated. The residue was dissolved in 15 ml oftetrahydrofuran and added dropwise at room temperature to a solution of3.3 g of ethyl 4-amino-benzoate in 80 ml of pyridine. After stirring for2 hours, the mixture was poured on to ice/water and extracted with ethylacetate. The organic phases were washed with 2N hydrochloric acid andwater, dried and evaporated. After recrystallization from ethylacetate/hexane, there were obtained 5.6 g of ethylp-(1,4-benzodioxane-6-carboxamido)benzoate, melting point 134°-136° C.

Hydrolysis of this ester with potassium hydroxide/water/ethanol at 50°C. during 2 hours yielded p-(1,4-benzodioxane-6-carboxamido)benzoicacid, melting point 278°-280° C.

EXAMPLE 63

32 g of [1-(4,4-dimethyl-6-thiochromanyl)ethyl]triphenylphosphoniumbromide were suspended in 130 ml of tetrahydrofuran and treated at 0° C.with 37 ml of n-butyllithium (1.6 molar in hexane). After stirring at 0°C. for 45 minutes, a solution of 10 g of4-(2-dimethylaminoethoxy)benzaldehyde in 60 ml of tetrahydrofuran wasadded dropwise to the orange reaction mixture. The mixture was stirredat room temperature for an additional 1 hour, poured on to ice/water andextracted with ether. The organic phases were washed with water, driedand evaporated. After filtration of the crude product over neutral Alox(eluting agent ether) and recrystallization from hexane/ether, therewere obtained 8.7 g of2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)propenyl]phenoxy]-N,N-dimethylethylamine,melting point 81°-82° C.

EXAMPLE 64

In analogy to Example 63, by reacting[1-(4,4-dimethyl-6-thiochromanyl)ethyl]triphenylphosphonium bromide with4-(2-morpholinoethoxy)benzaldehyde in a Wittig reaction, there wasprepared4-[2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl]propenyl]phenoxy]ethyl]morpholine,melting point 86°-88° C. (from ether/hexane).

EXAMPLE 65

In analogy to Example 63, by reacting[1-(4,4-dimethyl-6-thiochromanyl)ethyl]triphenylphosphonium bromide1,1-dioxide with 4-(2-dimethylaminoethoxy)benzaldehyde in a Wittigreaction, there was prepared2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)propenyl]phenoxy]-N,N-dimethylethylamine1,1-dioxide, melting point 121°-122° C. (from ether/hexane).

EXAMPLE 66

In analogy to Example 63, by reacting[1-(4,4-dimethyl-6-chromanyl)ethyl]triphenylphosphonium bromide with4-(2-dimethylaminoethoxy)benzaldehyde in a Wittig reaction, there wasprepared2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)propenyl]phenoxy]-N,N-dimethylethylamineas a colorless oil.

EXAMPLE 67

2.5 ml of Methyl iodide were dissolved in 30 ml of ether and addeddropwise under slight reflux to a suspension of 972 mg of magnesiumshavings in 15 ml of ether. After all of the magnesium had dissolved asolution of 6.2 g of 1,2,3,4-tetrahydro-1,4-dimethyl-6-formylquinoxalinein 15 ml of ether was added dropwise while cooling slightly. Afterstirring at room temperature for 3 hours, an aqueous solution ofammonium chloride was added dropwise while cooling with ice and thereaction mixture was subsequently extracted with ether. After drying andevaporation of the organic extracts, the crude product was purifiedfurther by flash chromatography (silica gel, eluting agent hexane/ethylacetate 1:1) and gave 6 g of a yellow oil.

This oil was dissolved in 300 ml of acetonitrile and 11 g oftriphenylphosphine hydrobromide were added. After stirring for 16 hours,the mixture was evaporated. The residue was dissolved in 300 ml ofethanol/water (8:2) and extracted several times with hexane. The aqueousphase was evaporated, dissolved in methylene chloride, again evaporated,again taken up with methylene chloride, dried over sodium sulfate andevaporated. There were obtained 12.4 g of a greenish, extremelyhygroscopic phosphonium salt as an amorphous powder.

10.3 g of this phosphonium salt were dissolved in 200 ml oftetrahydrofuran and treated at -78° C. with 19 ml of a 1.6 molarsolution of n-butyllithium in hexane. After stirring at -78° C. for 1hour, a solution of 5.1 g of methyl 4-formyl-benzoate in 30 ml oftetrahydrofuran was added dropwise thereto. The mixture was left to cometo room temperature and was stirred for an additional 2 hours. Afterworking-up in analogy to Example 3, the crude product was purified byflash chromatography (silica gel, eluting agent hexane/ethylacetate=4:1) and recrystallized from hexane. There were obtained 3.6 gof methylp-[(E)-2-(1,2,3,4-tetrahydro-1,4-dimethyl-6-quinoxalinyl)propenyl]-benzoatein the form of yellow crystals, melting point 91°-93° C.

600 mg of this ester were converted into the free acid by reaction witha solution of 1.5 g of potassium hydroxide in 25 ml of ethanol and 10 mlof water at 50° C. during 4 hours. After recrystallization from ethylacetate/hexane, there were obtained 450 mg ofp-[(E)-2-(1,2,3,4-tetrahydro-1,4-dimethyl-6-quinoxalinyl)propenyl]benzoicacid in the form of orange crystals, melting point 203°-205° C.

EXAMPLE 68

In analogy to Example 43, there were prepared:

p-(2,3,4,5-Tetrahydro-5-methyl-1-benzothiepine-8-carboxamido)benzoicacid, m.p. >270° C.;

p-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine-7-carboxamido)benzoicacid, m.p. >250° C.;

p-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine-7-carboxamido)benzoicacid, m.p. 261°-262° C.; and

p-(2,3,4,5-tetrahydro-1-benzothiepine-7-carboxamido)benzoic acid, m.p.249°-251° C.

EXAMPLE 69

The Grignard compound was prepared according to standard proceduresunder an argon atmosphere from 473 mg of magnesium shavings and 1.73 mlof benzyl chloride in 30 ml of tetrahydrofuran. Thereafter, 2.12 g ofundiluted 3,4-dihydro- 3,3-dimethyl-2H-1,5-benzodithiepin-7-yl methylketone were added thereto at 0° C. and the mixture was left to react atroom temperature for 1 hour. The mixture was hydrolyzed with NH₄ Clsolution, extracted with ether, washed with water, dried and evaporated.The thus-obtained crude product was taken up in 20 ml of toluene,treated with 500 mg of p-toluenesulfonic acid and stirred at 75° C.overnight. Dehydration and isomerization took place. The solvent wasremoved in a vacuum and the residue was purified by columnchromatography on silica gel (petroleum ether). Recrystallization fromhexane finally gave 1.75 g of3,4-dihydro-3,3-dimethyl-7-[(E)-α-methyl-styryl]-2H- 1,5-benzodithiepineas white crystals of melting point 76°-77° C.

3,4-Dihydro-3,3-dimethyl-7-[(E)-α-methylstyryl)-2H-1,5-benzodioxepine,melting point 45°-48° C., was prepared in an analogous manner.

EXAMPLE 70

The following are additional examples of compounds of formula I:

3,4-Dihydro-4,4-dimethyl-6-[(E)-α-methyl-p-[2-(tetrahydro-4'H-1,4-thiazin-4'-yl)ethoxy]styryl]-2H-1-benzothiopyran1',1'-dioxide, m.p. 153°-154° C.;

methyl p-[(E)-2-(2-methyl-1,3-benzodithiol-5-yl)propenyl]benzoate, m.p.72°-73° C. (hexane);

p-[(E)-2-(2-methyl-1,3-benzodithiol-5-yl)propenyl]benzoic acid, m.p.193°-195° C. (AcOEt);

ethyl p-(2,2-dimethyl-1,3-benzoxathiol-6-carboxamido)benzoate, m.p.137°-138° C.;

p-(2,2-dimethyl-1,3-benzoxathiol-6-carboxamido)benzoic acid, m.p.284°-286° C.;

ethyl p-(2,2-dimethyl-1,3-benzodioxol-6-carboxamido)benzoate, m.p.143°-144° C.;

2-[p-[(E)-3,4-(isopropylidenedioxy)-β-methylstyryl]phenoxy]-N,N-dimethylethylamine.m.p. 54°-56° C.;

6-[(E)-p-(3,3-dimethylbutoxy)-α-methylstyryl]-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran,m.p. 116°-117° C.;

p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl]propenyl]phenol,m.p. 84°-85° C.;

p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl]propenyl]phenol1,1-dioxide, m.p. 182° C.;

methylp-[(E)-2-(1,2,3,4-tetrahydro-1,2,3,4-tetramethyl-quinoxalin-6-yl)propenyl]benzoate,m.p. 90°-93° C.;

P-[(E)-2-(1,2,3,4-tetrahydro-1,2,3,4-tetramethylquinoxalin-6-yl)propenyl]benzoicacid, m.p. 199°-200° C.;

p-[(E)-2-(2,2-dimethyl-1,3-benzodioxol-5-yl)propenyl]benzoic acid, m.p.185°-196° C.;

p-(2,2-dimethyl-1,3-benzodioxol-5-carboxamido)benzoic acid, m.p.281°-283° C.;

ethylp-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)propenyl]phenylcarbonate, m.p. 113°-114° C.;

ethylp-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)propenyl]phenylcarbonate 1,1-dioxide, m.p. 130° C.; and

6-[(E)-p-methoxy-α-methylstyryl]-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran,m.p. 99°-100° C. (methanol);

The following compounds can also be prepared, and further illustrate thecompounds of formula I:

p-(1,4-benzodithiin-6-carboxamido)benzoic acid and its ethyl ester;

p-(1,2,3,4-tetrahydro-1,4-dimethyl-6-quinoxalinecarboxamido)benzoic acidand its ethyl ester;

p-(1,2,3,4-tetrahydro-1,2,3,4-tetramethyl-6-quinoxalinecarboxamido)benzoicacid and its ethyl ester;

4-(2-[p-[(E)-2-(1,2,3,4-tetrahydro-1,4,4-trimethylquinolin-6-yl]propenyl]phenoxy]ethyl]morpholine;

4-[2-[p-[(E)-2-(1,2,3,4-tetrahydro-1,4,4-trimethylquinolin-7-yl]propenyl]phenoxy]ethyl]morpholine;

4-[2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl]propenyl]phenoxy]ethyl]morpholine;

p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl]propenyl]phenol;

1,2,3,4-tetrahydro-1,4,4-trimethyl-4'-(2-morpholinoethoxy)-6-quinolinecarboxanilide;

4-[2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl]propenyl]phenoxy]ethyl]morpholine;

p-[2-(3,4-dihydio-4,4,6-trimethyl-2H-1-benzopyran-7-yl)propenyl]benzoicacid;

p-[1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl)carbamoyl]benzoicacid;

p-[2-(3,4-dihydro-4,4-dimethyl-6-methoxy-2H-1-benzothiopyran-7-yl)propenyl]benzoicacid; and

1-methyl-4-[2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)propenyl]phenoxy]ethyl]piperazine.

EXAMPLE A

Hard gelatin capsules can be prepared as follows:

    ______________________________________                                        Ingredients               mg/capsule                                          ______________________________________                                        1.    Spray-dried powder containing 75% of a                                                                200                                                   compound of formula I                                                   2.    Sodium dioctylsulfosuccinate                                                                          0.2                                             3.    Sodium carboxymethylcellulose                                                                         4.8                                             4.    Microcrystalline cellulose                                                                            86.0                                            5.    Talc                    8.0                                             6.    Magnesium stearate      1.0                                                   Total                   300                                             ______________________________________                                    

The spray-dried powder, which is based on the active ingredient, gelatinand microcrystalline cellulose, and which has an average particle sizeof the active ingredient of <1 mμ (measured by autocorrelationspectroscopy), is moistened with an aqueous solution of sodiumcarboxymethylcellulose and sodium dioctylsulfosuccinate and kneaded. Theresulting mass is granulated, dried and sieved, and the granulateobtained is mixed with microcrystalline cellulose, talc and magnesiumstearate. The powder is filled into size 0 capsules.

EXAMPLE B

Tablets can be prepared as follows:

    ______________________________________                                        Ingredients          mg/tablet                                                ______________________________________                                        1.     A compound of formula I as                                                                      500                                                         a finely milled Powder                                                 2.     Powdered lactose  100                                                  3.     White maize starch                                                                               60                                                  4.     Povidone K30*      8                                                   5.     White maize starch                                                                              112                                                  6.     Talc               16                                                  7.     Magnesium stearate                                                                               4                                                          Total             800                                                  ______________________________________                                         *a low viscosity grade polyvinylpyrrolidone                              

The finely milled active ingredient is mixed with lactose and a portionof the maize starch. The mixture is moistened with an aqueous solutionof Povidone K30 and kneaded, and the resulting mass is granulated, driedand sieved. The granulate is mixed with the remaining maize starch, talcand magnesium stearate and pressed into tablets of suitable size.

EXAMPLE C

Soft gelatin capsules can be prepared as follows:

    ______________________________________                                        Ingredients          mg/capsule                                               ______________________________________                                        1.      A compound of formula I                                                                         50                                                  2.      Triglyceride     450                                                                           500                                                  ______________________________________                                    

10 g of a compound of formula I are dissolved in 90 g of medium-chaintriglyceride with stirring, inert gasification and protection fromlight. This solution is processed as the capsule fill mass to give softgelatin capsules containing 50 mg of active ingredient.

EXAMPLE D

A solution can be prepared as follows:

    ______________________________________                                        Ingredients                                                                   ______________________________________                                        1.    A compound of formula I, finely milled                                                               3.0 g                                            2.    Carbopol 934           0.6 g                                            3.    Sodium hydroxide       q.s. ad pH 6                                     4.    94% ethanol            50.0 g                                           5.    Deionized water        100.0 g                                          ______________________________________                                    

The active ingredient is worked into the 94% ethanol/water mixture whileprotecting from light. Carbopol 934 is stirred in until gelling iscomplete and the pH value is adjusted with sodium hydroxide.

We claim:
 1. A compound of the formula ##STR10## wherein R¹ is hydrogen,acyl, lower-alkyl, --CHO, --CH₂ OR¹⁰, --COR⁷ or OR¹³ ; R², R³ and R⁴are, independently hydrogen, lower-alkyl, lower-alkoxy or halogen; R⁵and R⁶ are, independently, hydrogen or lower-alkyl; R⁷ is hydroxy,lower-alkoxy or NR⁸ R⁹ ; R⁸ and R⁹ are, independently, hydrogen orlower-alkyl; one of X and Y is >CR¹⁴ R¹⁵, and the other is --O--; R¹⁰ ishydrogen, lower-alkyl or acyl; M is --C(R¹¹)═C(R¹²)--, --CONH-- or--NH--CO--; R¹¹, R¹², R¹⁴ and R¹⁵ are, independently, hydrogen orlower-alkyl, R¹³ is hydrogen, lower-alkoxycarbonyl or lower-alkyl, whichcan be substituted by amino, mono-alkylamino, di-alkylamino, morpholino,thiomorpholino or piperazino, and n is 1, 2, 3 or 4 provided that R¹ isOR¹³ when M is --C(R¹¹)═C(R¹²)-- and R¹ is hydrogen, acyl, lower-alkyl,--CH₂ OR¹⁰, or OR¹³ when M is --CONH-- or a salt of a compound offormula I, when R¹ is carboxy.
 2. A compound in accordance with claim 1,wherein R¹³ is hydrogen or unsubstituted lower-alkyl or lower-alkylsubstituted by amino, mono-alkylamino, di-alkylamino, morpholino,thiomorpholino or piperazino.
 3. A compound in accordance with claim 2,wherein M is --C(R¹¹)═C(R¹²)--.
 4. A compound in accordance with claim2, wherein M is --CONH--.
 5. A compound in accordance with claim 3,wherein Y is --O--.
 6. A compound in accordance with claim 4, wherein Yis --O--.
 7. A compound of claim 1, wherein the compound is 3,4,-dihydro-4, 4-dimethyl-7-(α-methylstyryl)-2H-1-benzopyran.
 8. Acompound of claim 1, wherein the compound is4-[2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl]propenyl]phenoxy]ethyl]morpholine.9. A pharmaceutical composition comprising a compound of the formula##STR11## wherein R¹ is hydrogen, acyl, lower-alkyl, --CHO, --CH₂ OR¹⁰,--COR⁷ or OR¹³ ; R², R³ and R⁴ are, independently, hydrogen,lower-alkyl, lower-alkoxy or halogen; R⁵ and R⁶ are, independently,hydrogen or lower-alkyl; R⁷ is hydroxy, lower-alkoxy or NR⁸ R⁹ ; R⁸ andR⁹ are, independently, hydrogen or lower-alkyl; one of X and Y is >CR¹⁴R¹⁵, and the other is --O--; R¹⁰, is hydrogen, lower-alkyl or acyl; M is--C(R¹¹)═C(R¹²)--, --CONH-- or --NH--CO--; R¹¹, R¹², R¹⁴ and R¹⁵ are,independently, hydrogen or lower-alkyl, R¹³ is hydrogen,lower-alkoxycarbonyl or lower-alkyl, which can be substituted by amino,mono-alkylamino, di-alkylamino, morpholino, thiomorpholino orpiperazino, and n is 1, 2, 3 or 4 provided that R¹ is OR¹³ when M is--C(R¹¹)═C(R¹²)-- and R¹ is hydrogen, acyl, lower-alkyl, --CH₂ OR¹⁰, orOR¹³ when M is --CONH-- or a salt of a compound of formula I, when R¹ iscarboxy and an inert carrier.
 10. A pharmaceutical composition inaccordance with claim 9, wherein R¹³ is hydrogen or unsubstitutedlower-alkyl or lower-alkyl substituted by amino, mono-alkylamino,di-alkylamino, morpholino, thiomorpholino or piperazino.
 11. Apharmaceutical composition in accordance with claim 10, wherein M is--C(R¹¹)═C(R¹²)--.
 12. A pharmaceutical composition in accordance withclaim 10, wherein M is --CONH--.
 13. A pharmaceutical composition inaccordance with claim 11, wherein Y is --O--.
 14. A pharmaceuticalcomposition in accordance with claim 12, wherein Y is --O--.
 15. Amethod of treating inflammatory, allergic, rheumatic and immunologicaldisorders which comprises administering to a host requiring suchtreatment an effective amount of a compound of the formula ##STR12##wherein R¹ is hydrogen, acyl, lower-alkyl, --CHO, --CH₂ OR¹⁰, --COR⁷ orOR¹³ ; R², R³ and R⁴ are, independently, hydrogen, lower-alkyl,lower-alkoxy or halogen; R⁵ and R⁶ are, independently, hydrogen orlower-alkyl; R⁷ is hydroxy, lower-alkoxy or NR⁸ R⁹ ; R⁸ and R⁹ are,independently, hydrogen or lower-alkyl; one of X and Y is >CR¹⁴ R¹⁵, andthe other is --O-- R¹⁰ is hydrogen, lower-alkyl or acyl; M is--C(R¹¹)═C(R¹²)--, --CONH-- or --NH--CO--; R¹¹, R¹², R¹⁴ and R¹⁵ are,independently, hydrogen or lower-alkyl, R¹³ is hydrogen,lower-alkoxycarbonyl or lower-alkyl, which can be substituted by amino,mono-alkylamino, di-alkylamino, morpholino, thiomorpholino orpiperazino, and n is 1, 2, 3 or 4 provided that R¹ is OR¹³ when M is--C(R¹¹)═C(R¹²)-- and R¹ is hydrogen, acyl, lower-alkyl, --CH₂ OR¹⁰, orOR¹³ when M is --CONH-- or a salt of a compound of formula I, when R¹ iscarboxy.
 16. A method composition in accordance with claim 15, whereinR¹³ is hydrogen or unsubstituted lower-alkyl or lower-alkyl substitutedby amino, mono-alkylamino, di-alkylamino, morpholino, thiomorpholino orpiperazino.
 17. A method in accordance with claim 16, wherein M is--C(R¹¹)═C(R¹²)--.
 18. A method in accordance with claim 16, wherein Mis --CONH--.
 19. A method in accordance with claim 17, wherein Y is--O--.
 20. A method composition in accordance with claim 18, wherein Yis --O--.